<strong>Objective:</strong><span style="font-family:""><span style="font-family:Verdana;"> Breast cancer is a public health challenge on a global scale that is caused b...<strong>Objective:</strong><span style="font-family:""><span style="font-family:Verdana;"> Breast cancer is a public health challenge on a global scale that is caused by environmental or genetic factors. Breast cancer is affecting both males and females, but there is still a lack of effective drugs with improved potency and admissibility against breast cancer as many of the breast cancer drugs have severe side effects. </span><b><span style="font-family:Verdana;">Methods:</span></b><span style="font-family:Verdana;"> The docking approach has been used </span><span><span style="font-family:Verdana;">to find a new compound for breast cancer with more efficacy and tolerance and with lesser side effects. A ligand-based pharmacophore approach has been generated for 39 anticancer compounds with significance for the development of new drugs. </span><b><span style="font-family:Verdana;">Result:</span></b><span style="font-family:Verdana;"> Through docking, the approach found new lead compoun</span></span><span style="font-family:Verdana;">ds for breast cancer. The proposed pharmacophore model in this study contains two HBAs and one HYD</span></span><span style="font-family:Verdana;">,</span><span style="font-family:""><span style="font-family:Verdana;"> one hydrophobic domain </span><span style="font-family:Verdana;">and</span><span style="font-family:Verdana;"> two Aromatic rings</span></span><span style="font-family:""><span style="font-family:Verdana;"> and the estimated distance range is minimum to maxi</span><span style="font-family:Verdana;">mum of derived pharmacophore features.</span></span><span style="font-family:""> <b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> Based on this research, it is proposed that these two lead compounds may be able to be used against EGFR in breast cancer. New compounds can be identified based on common features in the Pharmacophore model. 3D pharmacophore triangle could be used for further studies because this pharmacophore has better merging and in the future for more studies can suggest the same distance range of pha</span></span><span style="font-family:Verdana;">rmacophore features as this pharmacophore.</span>展开更多
OBJECTIVE To employ pharmacophore modeling to identify a TACE inhibitor from an inhouse database of 66 organic compounds.METHODS To identify the common features required for TACE inhibition,we generated a pharmacophor...OBJECTIVE To employ pharmacophore modeling to identify a TACE inhibitor from an inhouse database of 66 organic compounds.METHODS To identify the common features required for TACE inhibition,we generated a pharmacophore model from a set of TACE-selective inhibitor using the Common Feature Pharmacophore Model protocol implemented in Discovery Studio 3.1.1.A fluorimetric assay was used to investigate the potential ability of compounds to inhibit TACE enzymatic activity.The ability of compound 1 to inhibit TACE activity in a human monocyte THP-1 cell line was evaluated by ELISA.RESULTS In this study,apharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds,from which compound 1 emerged as a top candidate.In a cell-free assay,compound 1inhibited TACE enzymatic activity in a dose-dependent manner.Moreover,compound 1 inhibited the production of soluble TNF-αin human acute monocytic leukemia THP-1 cells without impacting nitric oxide production,and exhibited anti-proliferative activity against THP-1cells.CONCLUSION Compound 1 was found to inhibit TACE enzymatic activity in a cell-free system and LPS-induced TNF-αsecretion in cellulo.We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors.展开更多
In the present study we investigated two groups of small molecular tyrosine kinascphosphory lation inhibilors (tyrphostins) with quite different structures (19 compounds of thebenzylidene malononitrile famliy and 13 c...In the present study we investigated two groups of small molecular tyrosine kinascphosphory lation inhibilors (tyrphostins) with quite different structures (19 compounds of thebenzylidene malononitrile famliy and 13 compounds of the 3-substituted indolin-2-ones family).With the aid of a pharmacophore analysis method (CATALYST). a common three-dimensionalpharmacophore model to these two kinds of molecules has been discovered. A better 3D-QSARanalysis based on the generaled pharmacophore model was conducted (correlate coeffcientR-0.956) and the model shows very good predictivc ability.展开更多
Coagulation Factor Xa(FXa)is the crucial enzyme at the convergent point of the intrinsic and extrinsic coagulation pathways.The inhibition of FXa is an effective approach against thrombotic diseases.In the present stu...Coagulation Factor Xa(FXa)is the crucial enzyme at the convergent point of the intrinsic and extrinsic coagulation pathways.The inhibition of FXa is an effective approach against thrombotic diseases.In the present study,a specific strategy is reported to discover 10 novel FXa inhibitors based on ligand-based(pharmacophore)virtual screening and molecular docking analysis from a dataset of specs(containing 220000 molecules).The binding modes analysis provide insights into the contribution of particular structural moieties of the compounds towards their activity against FXa,and 10 novel structural compounds were discovered as potent candidate molecules.This work could be helpful in further design and development of FXa inhibitors.展开更多
CDK<span style="white-space:nowrap;"><sub></span></span><sub><span style="font-family:Verdana;">2<span style="white-space:nowrap;"></sub>&l...CDK<span style="white-space:nowrap;"><sub></span></span><sub><span style="font-family:Verdana;">2<span style="white-space:nowrap;"></sub></span></span></sub><span style="font-family:Verdana;"> is one of the most important members of Cyclin-dependent kinases. It is a critical modulator of various oncogenic signaling pathways, and its activity is vital for </span><span style="font-family:Verdana;">loss</span><span style="font-family:Verdana;"> of proliferative control during oncogenesis. This work has focused on developing a pharmacophore model for CDK<span style="white-space:nowrap;"><sub></span></span><sub><span style="font-family:Verdana;">2<span style="white-space:nowrap;"></sub></span></span></sub><span style="font-family:Verdana;"> inhibitors by using a dataset of known inhibitors as a pre-filter throughout the virtual screening and docking process. Consequently, the best pharmacophore model was made of one hydrogen bond acceptor, and two aromatic ring features with </span></span><span style="font-family:Verdana;">a </span><span style="font-family:Verdana;">high</span><span style="font-family:""><span style="font-family:Verdana;"> correlation value of 0.906. The validation findings proved out that the selected model can be used as a filter to screen new molecules like Enamine kinase hinge region directed library against CDK<span style="white-space:nowrap;"><sub></span></span><sub><span style="font-family:Verdana;">2<span style="white-space:nowrap;"></sub></span><strong></strong></span></sub><span style="font-family:Verdana;">. As a result, 69 hits were subjected to molecular docking studies. Eventually, three compounds</span></span><span style="font-family:Verdana;"> (</span><span style="font-family:""><span style="font-family:Verdana;">5909, 701 </span><span style="font-family:Verdana;">and</span><span style="font-family:Verdana;"> 8397</span></span><span style="font-family:Verdana;">) </span><span style="font-family:""><span style="font-family:Verdana;">scored good interaction energy values and strong molecular interactions. Hence, they were identified as leads for novel CDK<span style="white-space:nowrap;"><sub></span></span><sub><span style="font-family:Verdana;">2<strong><span style="white-space:nowrap;"></sub></span></strong></span></sub><span style="font-family:Verdana;"> inhibitors as anticancer drugs.展开更多
Various recent reports on Tuberculosis have alarmed an increase in the patient class and subsequent death rates across the globe. Over and above the spread of more dangerous and fatal forms of tuberculosis like MDR-TB...Various recent reports on Tuberculosis have alarmed an increase in the patient class and subsequent death rates across the globe. Over and above the spread of more dangerous and fatal forms of tuberculosis like MDR-TB i.e. multiple-drug resistance tuberculosis, XDR-TB i.e. extensively-drug resistance tuberculosis & TDR-TB i.e. total-drug resistance tuberculosis has forwarded an urgent need to discover novel antitubercular agents. The current work is aimed at combining two previously well-known pharmacophores (pyrazoline and benzoxazole nucleus) in order to design and synthesize a series of novel benzoxazole-based pyrazoline derivatives. The synthesized target compounds were structurally confirmed by LCMS, 1H-NMR and 13C-NMR analysis. The target compounds were In vitro evaluated against M. tuberculosis H37Rv strain, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. The In vitro screening results depicted that majority of the target compounds displayed potent activity with MIC in a range of ~0.8 to 6.25 μg/mL. Many compounds were found to be more potent than isoniazid against MDR-TB with MIC value 3.12 μg/mL and XDR-TB with MIC value 12.5 μg/mL. Cytotoxicity assay of these active compounds on VERO cell lines also displayed good selectivity index.展开更多
Thrombin, an important factor of clotting system, take part in a variety of physiological actions, such as blood clotting, anticoagulation, thrombosis and fibrinolysis. Inhibiting thrombin is a pivotal and effective s...Thrombin, an important factor of clotting system, take part in a variety of physiological actions, such as blood clotting, anticoagulation, thrombosis and fibrinolysis. Inhibiting thrombin is a pivotal and effective step for the prophylaxis of venous and arterial thrombosis, as well as prevent myocardial infarction for high-risk patients. In this study, a three dimensional pharmacophore model was generated for the molecules which are responsible for vasodilation activities targeting thrombin. Ten compounds with known thrombin-inhibiting activity values were selected as training set to generate the hypothesis using GALAHAD program in SYBYL 7.0 software. The best hypothesis comprises five pharmacophore features: four hydrophobes groups and one positively charged group. It has been further validated towards a test set including known activity compounds obtained from Binding Database, the values of effectively active hit A% and comprehensive evaluation index CAI are respectively 63.33% and 2.34, the pharmacophore was proven to be successful in discriminating active and inactive inhibitors. ?Furthermore, the pharmacophore model was used as a 3D query to screen TCMD (Version 2009) database and 6 hit compounds of higher predicted activity were the reported cardiovascular activities, which may be useful for further study.展开更多
DNA methyltransferase 1 (DNMT1), one of the main epigenetic targets, is involved in the duplication of the DNA methylation pattern during replication, and it is essential for proper mammalian development. Small molecu...DNA methyltransferase 1 (DNMT1), one of the main epigenetic targets, is involved in the duplication of the DNA methylation pattern during replication, and it is essential for proper mammalian development. Small molecule DNMT1 modulators are attractive for biochemical epigenetic studies and have the potential to become drugs. So far, more than five hundred small molecules have been reported as DNMT1 inhibitors. However, only a limited number of DNMT1 activators have been disclosed because, at least in part, DNMT1 activators are typically regarded as negative data in virtual screening campaigns or optimization projects. This manuscript aims to report the chemical structures and biological activity of small molecules that increase the enzymatic activity of DNMT1. Results of the biochemical experimental assays are discussed. It was found that small molecule activators have a large variety of chemical scaffolds but share pharmacophore features. Visual analysis of the chemical space and multiverse based on molecular fingertips supported that activators are structurally diverse. This is the first report of eight small molecules that increase the enzymatic activity of DNMT1 by more than 400% in an enzymatic-based assay. The outcome warrants further investigation of the epigenetic activity of the compounds in a counter-screen assay, e.g., cell-based and in vivo context.展开更多
Anticancer targets of cryptotanshinone were evaluated and rapidly forecasted with PharmMapper, a reverse pharmacophore-based screening platform, as well as drug target databases, including PDTD, DrugBank and TTD. The ...Anticancer targets of cryptotanshinone were evaluated and rapidly forecasted with PharmMapper, a reverse pharmacophore-based screening platform, as well as drug target databases, including PDTD, DrugBank and TTD. The pathway analyses for the collection of anticancer targets screened were carried out based on the KEGG pathway database, followed by the forecast of potential pharmacological activities and pathways of the effects of cryptotanshinone, and verification of some of the targets screened using whole cell tests. The results showed that a total of eight targets with anticancer potential were screened, including MAP2K1, RARα, RXRα, PDK1, CHK1, AR, Ang-1 R, and Kif11. These targets are mainly related to four aspects of the cancer growth: the cell cycle, angiogenesis, apoptosis, and androgen receptor. The cell tests showed that cryptotanshinone can inhibit the viability of human hepatoma cells SMMC-7721, which is related to the reduction of expression of MAP2K1 mRNA. This method provides a strong clue for the study of the anticancer effects and mechanisms of action of cryptotanshinone in the future.展开更多
Chemical feature based pharmacophore models were generated for an angiotensin converting enzyme(ACE) inhibitory peptide using the Discovery Studio 2.0 pharmacophore modeling approach. The pharmacophore hypothesis sele...Chemical feature based pharmacophore models were generated for an angiotensin converting enzyme(ACE) inhibitory peptide using the Discovery Studio 2.0 pharmacophore modeling approach. The pharmacophore hypothesis selected has five features(one negative ionizable region,one hydrogen bond donor,one hydrogen bond acceptor and two hydrophobic functional groups). Additionally,ACE inhibitory hexapeptide previously obtained from silkworm pupae protein was optimized to target the ACE based on the selected pharmacophore. The results suggest that tri-peptide(thr-val-phe) may be structural determinant of ACE activity. Docking studies further provided confidence for the validity of the selected pharmacophore model to perform structure optimization of the ACE inhibitory peptide.展开更多
We herein describe AncPhore,a versatile tool for drug discovery,which is characterized by pharmacophore feature analysis and anchor pharmacophore(i.e.,most important pharmacophore features)steered molecular fitting an...We herein describe AncPhore,a versatile tool for drug discovery,which is characterized by pharmacophore feature analysis and anchor pharmacophore(i.e.,most important pharmacophore features)steered molecular fitting and virtual screening.Comparative analyses of numerous protein-ligand complexes using AncPhore revealed that anchor pharmacophore features are biologically important,commonly associated with protein conservative characteristics,and have significant contributions to the binding affinity.Performance evaluation of AncPhore showed that it had substantially improved prediction ability on different types of target proteins including metalloenzymes by considering the specific contributions and diversity of anchor pharmacophore features.To demonstrate the practicability of AncPhore,we screened commercially available chemical compounds and discovered a set of structurally diverse inhibitors for clinically relevant metallo-β-lactamases(MBLs);of them,4 and 6 manifested potent inhibitory activity to VIM-2,NDM-1 and IMP-1 MBLs.Crystallographic analyses of VIM-2:4 complex revealed the precise inhibition mode of 4 with VIM-2,highly consistent with the defined anchor pharmacophore features.Besides,we also identified new hit compounds by using AncPhore for indoleamine/tryptophan 2,3-dioxygenases(IDO/TDO),another class of clinically relevant metalloenzymes.This work reveals anchor pharmacophore as a valuable concept for target-centered drug discovery and illustrates the potential of AncPhore to efficiently identify new inhibitors for different types of protein targets.展开更多
The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused...The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused on exploring the SAR for inhibitors of the LTA4 hydrolase through docking study, pharmacophore modeling and molecular descriptor study. The binding of these small molecules on LTA4 hydrolase enzyme was described by the models developed on 2D molecular descriptors, with good predictive power (39 compounds, 6 descriptors, r2 0.98, SEE 0.167, F-value 268.53, q2 0.90, r2adj 0.97, P-value < 0.0001, SD of residuals 0.15). Docking studies were employed to presume the probable binding conformation of these analogues and exploring the SAR for the compounds. The novel pharmacophore represents the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The efforts are aimed to discover the SAR for the inhibitors of LTA4 hydrolase through techniques of QSAR, docking and pharmacophore.展开更多
A predictive pharmacophore model has been generated from a series of diverse fatty acid amide hydrolase(FAAH)inhibitors and the optimal pharmacophore model applied in virtual screening.The pharmacophore model was base...A predictive pharmacophore model has been generated from a series of diverse fatty acid amide hydrolase(FAAH)inhibitors and the optimal pharmacophore model applied in virtual screening.The pharmacophore model was based on a training set of 21 compounds carefully selected from the published literatures.The optimal model Hypo-1 included four features(two hydrogen-bond acceptor units,one aromatic hydrophobic unit and one aromatic ring unit)and two excluded volumes.Cross-validation of the model confirmed that Hypo-1 was not generated by chance correlation.A large test set of 55 compounds showed that Hypo-1 performed well in classifying highly active and less active FAAH inhibitors.Superimposition analysis of the FAAH X-ray crystal structure and the pharmacophore Hypo-1 further validated the adequacy of the model.Virtual screening generated a total of 976 hits from the Zinc Natural Products database,a hit rate of 1.04%and enrichment of 83.89.The acceptable hit rate further supports the use of Hypo-1 as a 3D query tool for virtual screening.展开更多
Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane protein responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule. Inhibition of hSGLT2 has been regarded as a brand new thera...Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane protein responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule. Inhibition of hSGLT2 has been regarded as a brand new therapeutic approach for the treatment of type 2 diabetes mellitus (T2DM) due to its non-insulin related characteristics with less side effects. Current commercially available hSGLT2 inhibitors are all C-glycoside inhibitors. Previous studies have reported that N-glycoside inhibitors have better potential to serve as new drugs due to their good metabolic stability. In addition, non-glycoside inhibitors have been shown to exhibit the capability to overcome the existing problems of current glycoside inhibitors, including low tissue permeability, poor stability and short serum half-time. Here, we aimed to discover novel N-glycoside and non-glycoside hSGLT2 inhibitors by a combination of several computational approaches. A ligand-based pharmacophore model was generated, well validated and subsequently utilized as a 3D query to identify novel hSGLT2 inhibitors from National Cancer Institute (NCI) and Traditional Chinese Medicine (TCM) databases. Finally, one N-glycoside (NSC679207) and one non-glycoside (TCM_Piperenol_A) hSGLT2 inhibitors were successfully identified, which were proven to exhibit excellent binding affinities, pharmacokinetic properties and less toxicity than the commercially available hSGLT2 inhibitor, canagliflozin, via molecular docking, ADMET prediction, molecular dynamics (MD) simulations and binding free energy calculations. All together, our results strongly suggest that these two compounds have great potential to serve as novel hSGLT2 inhibitors for the treatment of T2DM and their efficacies may be further examined by a series of in vitro and/or in vivo bioassays.展开更多
OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key target...OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key targets toward Alzheimer disease.Then,druglikeness,oral bioavailability and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for central nervous system diseases treatment.Finallly,we were attempted to predict the targets of constituents and find potential multi-target compounds from Nao De Sheng formula by combining the advantages of machine learning,molecular docking and pharmacophore mapping together.RESULTS Constituenttarget network,constituent-target-target network and targetbiological pathway network were built to explain the network pharmacology of the constituents in NaoD eS heng formula.CONCLUSION To the best of our knowledge,we were the first to study the mechanism of Nao De Sheng formula for potential efficacy for Alzheimer disease treatment by means of the virtual screening and network pharmacology methods.展开更多
Natural products are characterized with diverse structures and biological activities. They show a certain degree of adaptability to human beings. However, they need to be modified to increase their druggability. Sever...Natural products are characterized with diverse structures and biological activities. They show a certain degree of adaptability to human beings. However, they need to be modified to increase their druggability. Several strategies including pharmacophore similarity, physicochemical property optimization, and bioactivity focus may help to make them more drug-like candidates.展开更多
Objective:Explicating the property and action of traditional Chinese medicine(TCM)in the perspectives of modern science deepens the insight into the property of TCM,and provides the basis for new drug discovery and cl...Objective:Explicating the property and action of traditional Chinese medicine(TCM)in the perspectives of modern science deepens the insight into the property of TCM,and provides the basis for new drug discovery and clinical therapy.In this study,we investigated the relationship between transient receptor potential melastatin 8(TRPM8)and pungent flavor using three-dimensional pharmacophores based on virtual screening methods.Methods:Firstly,an inhouse database was established to identify the related pharmacological action according to the traditional Chinese herbs expressing an action of promoting blood circulation.Then,several therapeutic targets,3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-CoAR),cholesteryl ester transfer protein(CETP),Niemann-Pick C1-Like 1(NPC1L1)and platelet-activating factor receptor(PAFR),were selected to screen traditional Chinese herbs,and the common virtual screening hits with various hit scores providing data to reveal the correlation among TRPM8 and therapeutic targets.Results:According to the screening results,TRPM8 agonists were able to identify the effective components of pungent herbs and TRPM8,which shares the common virtual screening hits with the therapeutic targets,was considered to be related to the action of pungent taste.Conclusion:The novel ideas and methods in this study are beneficial to unveil the scientific relationship between a TCM property and its action.展开更多
Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase...Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.展开更多
It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approve...It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors by carrying out structural modifications and optimizations in future studies.展开更多
A new class of potential antibacterial agents has been synthesized on a new molecular scaffold of cyclohexane carboxylate. We have tagged this new class of compounds TACCs (Trisubstituted Aryl Cyclohexanecarboxylate)....A new class of potential antibacterial agents has been synthesized on a new molecular scaffold of cyclohexane carboxylate. We have tagged this new class of compounds TACCs (Trisubstituted Aryl Cyclohexanecarboxylate). These new molecules are structural analogues of an Activators of Self-Compartmentalizing Proteases 4 and 5 (ACP 4 and 5), and were synthesized to circumvent the drug-like property (drug-ability) challenges and liability noted in ACP 4 and 5. A pseudo-Robinson annulation protocol was used to furnish this new class of potential antibiotics. Structure-activity relationship (SAR) study was done to identify the pharmacophore(s) in this molecular scaffold. A selection of these compounds was used in our preliminary antibacterial inhibitory activities’ studies on Bacillus mycoides and Bacillus subtilis. These preliminary studies show that the TACCs exhibited equal, and in some cases better, antibacterial activity than ACP 4 and 5.展开更多
文摘<strong>Objective:</strong><span style="font-family:""><span style="font-family:Verdana;"> Breast cancer is a public health challenge on a global scale that is caused by environmental or genetic factors. Breast cancer is affecting both males and females, but there is still a lack of effective drugs with improved potency and admissibility against breast cancer as many of the breast cancer drugs have severe side effects. </span><b><span style="font-family:Verdana;">Methods:</span></b><span style="font-family:Verdana;"> The docking approach has been used </span><span><span style="font-family:Verdana;">to find a new compound for breast cancer with more efficacy and tolerance and with lesser side effects. A ligand-based pharmacophore approach has been generated for 39 anticancer compounds with significance for the development of new drugs. </span><b><span style="font-family:Verdana;">Result:</span></b><span style="font-family:Verdana;"> Through docking, the approach found new lead compoun</span></span><span style="font-family:Verdana;">ds for breast cancer. The proposed pharmacophore model in this study contains two HBAs and one HYD</span></span><span style="font-family:Verdana;">,</span><span style="font-family:""><span style="font-family:Verdana;"> one hydrophobic domain </span><span style="font-family:Verdana;">and</span><span style="font-family:Verdana;"> two Aromatic rings</span></span><span style="font-family:""><span style="font-family:Verdana;"> and the estimated distance range is minimum to maxi</span><span style="font-family:Verdana;">mum of derived pharmacophore features.</span></span><span style="font-family:""> <b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> Based on this research, it is proposed that these two lead compounds may be able to be used against EGFR in breast cancer. New compounds can be identified based on common features in the Pharmacophore model. 3D pharmacophore triangle could be used for further studies because this pharmacophore has better merging and in the future for more studies can suggest the same distance range of pha</span></span><span style="font-family:Verdana;">rmacophore features as this pharmacophore.</span>
基金The project supported by Hong Kong Baptist University(FRG2/12-13/021and FRG2/13-14/008)Centre for Cancer and Inflammation Research,School of Chinese Medicine(CCIR-SCM,HKBU)+5 种基金the Health and Medical Research Fund(HMRF/13121482)the Research Grants Council(HKBU/201811,HKBU/204612,and HKBU/201913)the French National Research Agency/Research Grants Council Joint Research Scheme(A-HKBU201/12)the Science and Technology Development Fund,Macao SAR(103/2012/A3)the University of Macao〔MYRG091(Y3-L2)-ICMS12-LCH,MYRG121(Y3-L2)-ICMS12-LCH and MRG023/LCH/2013/ICMS〕and University Research Committee Grant(RG55/06)from Nanyang Technological University and a Science and Engineering Research Council Grant(092 101 0053)from A*STAR,Singapore
文摘OBJECTIVE To employ pharmacophore modeling to identify a TACE inhibitor from an inhouse database of 66 organic compounds.METHODS To identify the common features required for TACE inhibition,we generated a pharmacophore model from a set of TACE-selective inhibitor using the Common Feature Pharmacophore Model protocol implemented in Discovery Studio 3.1.1.A fluorimetric assay was used to investigate the potential ability of compounds to inhibit TACE enzymatic activity.The ability of compound 1 to inhibit TACE activity in a human monocyte THP-1 cell line was evaluated by ELISA.RESULTS In this study,apharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds,from which compound 1 emerged as a top candidate.In a cell-free assay,compound 1inhibited TACE enzymatic activity in a dose-dependent manner.Moreover,compound 1 inhibited the production of soluble TNF-αin human acute monocytic leukemia THP-1 cells without impacting nitric oxide production,and exhibited anti-proliferative activity against THP-1cells.CONCLUSION Compound 1 was found to inhibit TACE enzymatic activity in a cell-free system and LPS-induced TNF-αsecretion in cellulo.We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors.
文摘In the present study we investigated two groups of small molecular tyrosine kinascphosphory lation inhibilors (tyrphostins) with quite different structures (19 compounds of thebenzylidene malononitrile famliy and 13 compounds of the 3-substituted indolin-2-ones family).With the aid of a pharmacophore analysis method (CATALYST). a common three-dimensionalpharmacophore model to these two kinds of molecules has been discovered. A better 3D-QSARanalysis based on the generaled pharmacophore model was conducted (correlate coeffcientR-0.956) and the model shows very good predictivc ability.
基金the Science and Technology Innovation Talent Project of Sichuanprovince (Grant number 2016073).
文摘Coagulation Factor Xa(FXa)is the crucial enzyme at the convergent point of the intrinsic and extrinsic coagulation pathways.The inhibition of FXa is an effective approach against thrombotic diseases.In the present study,a specific strategy is reported to discover 10 novel FXa inhibitors based on ligand-based(pharmacophore)virtual screening and molecular docking analysis from a dataset of specs(containing 220000 molecules).The binding modes analysis provide insights into the contribution of particular structural moieties of the compounds towards their activity against FXa,and 10 novel structural compounds were discovered as potent candidate molecules.This work could be helpful in further design and development of FXa inhibitors.
文摘CDK<span style="white-space:nowrap;"><sub></span></span><sub><span style="font-family:Verdana;">2<span style="white-space:nowrap;"></sub></span></span></sub><span style="font-family:Verdana;"> is one of the most important members of Cyclin-dependent kinases. It is a critical modulator of various oncogenic signaling pathways, and its activity is vital for </span><span style="font-family:Verdana;">loss</span><span style="font-family:Verdana;"> of proliferative control during oncogenesis. This work has focused on developing a pharmacophore model for CDK<span style="white-space:nowrap;"><sub></span></span><sub><span style="font-family:Verdana;">2<span style="white-space:nowrap;"></sub></span></span></sub><span style="font-family:Verdana;"> inhibitors by using a dataset of known inhibitors as a pre-filter throughout the virtual screening and docking process. Consequently, the best pharmacophore model was made of one hydrogen bond acceptor, and two aromatic ring features with </span></span><span style="font-family:Verdana;">a </span><span style="font-family:Verdana;">high</span><span style="font-family:""><span style="font-family:Verdana;"> correlation value of 0.906. The validation findings proved out that the selected model can be used as a filter to screen new molecules like Enamine kinase hinge region directed library against CDK<span style="white-space:nowrap;"><sub></span></span><sub><span style="font-family:Verdana;">2<span style="white-space:nowrap;"></sub></span><strong></strong></span></sub><span style="font-family:Verdana;">. As a result, 69 hits were subjected to molecular docking studies. Eventually, three compounds</span></span><span style="font-family:Verdana;"> (</span><span style="font-family:""><span style="font-family:Verdana;">5909, 701 </span><span style="font-family:Verdana;">and</span><span style="font-family:Verdana;"> 8397</span></span><span style="font-family:Verdana;">) </span><span style="font-family:""><span style="font-family:Verdana;">scored good interaction energy values and strong molecular interactions. Hence, they were identified as leads for novel CDK<span style="white-space:nowrap;"><sub></span></span><sub><span style="font-family:Verdana;">2<strong><span style="white-space:nowrap;"></sub></span></strong></span></sub><span style="font-family:Verdana;"> inhibitors as anticancer drugs.
文摘Various recent reports on Tuberculosis have alarmed an increase in the patient class and subsequent death rates across the globe. Over and above the spread of more dangerous and fatal forms of tuberculosis like MDR-TB i.e. multiple-drug resistance tuberculosis, XDR-TB i.e. extensively-drug resistance tuberculosis & TDR-TB i.e. total-drug resistance tuberculosis has forwarded an urgent need to discover novel antitubercular agents. The current work is aimed at combining two previously well-known pharmacophores (pyrazoline and benzoxazole nucleus) in order to design and synthesize a series of novel benzoxazole-based pyrazoline derivatives. The synthesized target compounds were structurally confirmed by LCMS, 1H-NMR and 13C-NMR analysis. The target compounds were In vitro evaluated against M. tuberculosis H37Rv strain, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. The In vitro screening results depicted that majority of the target compounds displayed potent activity with MIC in a range of ~0.8 to 6.25 μg/mL. Many compounds were found to be more potent than isoniazid against MDR-TB with MIC value 3.12 μg/mL and XDR-TB with MIC value 12.5 μg/mL. Cytotoxicity assay of these active compounds on VERO cell lines also displayed good selectivity index.
文摘Thrombin, an important factor of clotting system, take part in a variety of physiological actions, such as blood clotting, anticoagulation, thrombosis and fibrinolysis. Inhibiting thrombin is a pivotal and effective step for the prophylaxis of venous and arterial thrombosis, as well as prevent myocardial infarction for high-risk patients. In this study, a three dimensional pharmacophore model was generated for the molecules which are responsible for vasodilation activities targeting thrombin. Ten compounds with known thrombin-inhibiting activity values were selected as training set to generate the hypothesis using GALAHAD program in SYBYL 7.0 software. The best hypothesis comprises five pharmacophore features: four hydrophobes groups and one positively charged group. It has been further validated towards a test set including known activity compounds obtained from Binding Database, the values of effectively active hit A% and comprehensive evaluation index CAI are respectively 63.33% and 2.34, the pharmacophore was proven to be successful in discriminating active and inactive inhibitors. ?Furthermore, the pharmacophore model was used as a 3D query to screen TCMD (Version 2009) database and 6 hit compounds of higher predicted activity were the reported cardiovascular activities, which may be useful for further study.
文摘DNA methyltransferase 1 (DNMT1), one of the main epigenetic targets, is involved in the duplication of the DNA methylation pattern during replication, and it is essential for proper mammalian development. Small molecule DNMT1 modulators are attractive for biochemical epigenetic studies and have the potential to become drugs. So far, more than five hundred small molecules have been reported as DNMT1 inhibitors. However, only a limited number of DNMT1 activators have been disclosed because, at least in part, DNMT1 activators are typically regarded as negative data in virtual screening campaigns or optimization projects. This manuscript aims to report the chemical structures and biological activity of small molecules that increase the enzymatic activity of DNMT1. Results of the biochemical experimental assays are discussed. It was found that small molecule activators have a large variety of chemical scaffolds but share pharmacophore features. Visual analysis of the chemical space and multiverse based on molecular fingertips supported that activators are structurally diverse. This is the first report of eight small molecules that increase the enzymatic activity of DNMT1 by more than 400% in an enzymatic-based assay. The outcome warrants further investigation of the epigenetic activity of the compounds in a counter-screen assay, e.g., cell-based and in vivo context.
基金supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(No.11KJB360004)the Jiangsu Provincial Natural Science Foundation of China(No.BK2012458),the National Natural Science Foundation of China(Nos.81373232,81173174,81270514)+1 种基金the National Key Technology R&D Program during the 11th Five-Year Plan Period(No.2008BAI51B02)the Doctoral Fund of Ministry of Education of China(No.20113237110008)
文摘Anticancer targets of cryptotanshinone were evaluated and rapidly forecasted with PharmMapper, a reverse pharmacophore-based screening platform, as well as drug target databases, including PDTD, DrugBank and TTD. The pathway analyses for the collection of anticancer targets screened were carried out based on the KEGG pathway database, followed by the forecast of potential pharmacological activities and pathways of the effects of cryptotanshinone, and verification of some of the targets screened using whole cell tests. The results showed that a total of eight targets with anticancer potential were screened, including MAP2K1, RARα, RXRα, PDK1, CHK1, AR, Ang-1 R, and Kif11. These targets are mainly related to four aspects of the cancer growth: the cell cycle, angiogenesis, apoptosis, and androgen receptor. The cell tests showed that cryptotanshinone can inhibit the viability of human hepatoma cells SMMC-7721, which is related to the reduction of expression of MAP2K1 mRNA. This method provides a strong clue for the study of the anticancer effects and mechanisms of action of cryptotanshinone in the future.
基金Supported by the Program 111 of Ministry of Education of China and the Program "National Science and Technology Support Plan of Eleventh Five Year Program-ming" of China (Grant No. 2006BAD05A01)
文摘Chemical feature based pharmacophore models were generated for an angiotensin converting enzyme(ACE) inhibitory peptide using the Discovery Studio 2.0 pharmacophore modeling approach. The pharmacophore hypothesis selected has five features(one negative ionizable region,one hydrogen bond donor,one hydrogen bond acceptor and two hydrophobic functional groups). Additionally,ACE inhibitory hexapeptide previously obtained from silkworm pupae protein was optimized to target the ACE based on the selected pharmacophore. The results suggest that tri-peptide(thr-val-phe) may be structural determinant of ACE activity. Docking studies further provided confidence for the validity of the selected pharmacophore model to perform structure optimization of the ACE inhibitory peptide.
基金supported by the funds from the National Natural Science Foundation of China(81874291,82073698,and 81502989)the Sichuan Science and Technology Program(2018HH0100,China)+1 种基金111 project(B18035,China)Outstanding Interdiscipline Project of West China Hospital of Sichuan University(ZYJC18024,China)
文摘We herein describe AncPhore,a versatile tool for drug discovery,which is characterized by pharmacophore feature analysis and anchor pharmacophore(i.e.,most important pharmacophore features)steered molecular fitting and virtual screening.Comparative analyses of numerous protein-ligand complexes using AncPhore revealed that anchor pharmacophore features are biologically important,commonly associated with protein conservative characteristics,and have significant contributions to the binding affinity.Performance evaluation of AncPhore showed that it had substantially improved prediction ability on different types of target proteins including metalloenzymes by considering the specific contributions and diversity of anchor pharmacophore features.To demonstrate the practicability of AncPhore,we screened commercially available chemical compounds and discovered a set of structurally diverse inhibitors for clinically relevant metallo-β-lactamases(MBLs);of them,4 and 6 manifested potent inhibitory activity to VIM-2,NDM-1 and IMP-1 MBLs.Crystallographic analyses of VIM-2:4 complex revealed the precise inhibition mode of 4 with VIM-2,highly consistent with the defined anchor pharmacophore features.Besides,we also identified new hit compounds by using AncPhore for indoleamine/tryptophan 2,3-dioxygenases(IDO/TDO),another class of clinically relevant metalloenzymes.This work reveals anchor pharmacophore as a valuable concept for target-centered drug discovery and illustrates the potential of AncPhore to efficiently identify new inhibitors for different types of protein targets.
基金Project supported by Department of Science and Technology,Govt.of India for Awarding Young Scientist Fellowship (SR/FT/LS-161/2008)
文摘The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused on exploring the SAR for inhibitors of the LTA4 hydrolase through docking study, pharmacophore modeling and molecular descriptor study. The binding of these small molecules on LTA4 hydrolase enzyme was described by the models developed on 2D molecular descriptors, with good predictive power (39 compounds, 6 descriptors, r2 0.98, SEE 0.167, F-value 268.53, q2 0.90, r2adj 0.97, P-value < 0.0001, SD of residuals 0.15). Docking studies were employed to presume the probable binding conformation of these analogues and exploring the SAR for the compounds. The novel pharmacophore represents the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The efforts are aimed to discover the SAR for the inhibitors of LTA4 hydrolase through techniques of QSAR, docking and pharmacophore.
基金supported by the National Science Foundation of China(Grant No.40976050)。
文摘A predictive pharmacophore model has been generated from a series of diverse fatty acid amide hydrolase(FAAH)inhibitors and the optimal pharmacophore model applied in virtual screening.The pharmacophore model was based on a training set of 21 compounds carefully selected from the published literatures.The optimal model Hypo-1 included four features(two hydrogen-bond acceptor units,one aromatic hydrophobic unit and one aromatic ring unit)and two excluded volumes.Cross-validation of the model confirmed that Hypo-1 was not generated by chance correlation.A large test set of 55 compounds showed that Hypo-1 performed well in classifying highly active and less active FAAH inhibitors.Superimposition analysis of the FAAH X-ray crystal structure and the pharmacophore Hypo-1 further validated the adequacy of the model.Virtual screening generated a total of 976 hits from the Zinc Natural Products database,a hit rate of 1.04%and enrichment of 83.89.The acceptable hit rate further supports the use of Hypo-1 as a 3D query tool for virtual screening.
文摘Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane protein responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule. Inhibition of hSGLT2 has been regarded as a brand new therapeutic approach for the treatment of type 2 diabetes mellitus (T2DM) due to its non-insulin related characteristics with less side effects. Current commercially available hSGLT2 inhibitors are all C-glycoside inhibitors. Previous studies have reported that N-glycoside inhibitors have better potential to serve as new drugs due to their good metabolic stability. In addition, non-glycoside inhibitors have been shown to exhibit the capability to overcome the existing problems of current glycoside inhibitors, including low tissue permeability, poor stability and short serum half-time. Here, we aimed to discover novel N-glycoside and non-glycoside hSGLT2 inhibitors by a combination of several computational approaches. A ligand-based pharmacophore model was generated, well validated and subsequently utilized as a 3D query to identify novel hSGLT2 inhibitors from National Cancer Institute (NCI) and Traditional Chinese Medicine (TCM) databases. Finally, one N-glycoside (NSC679207) and one non-glycoside (TCM_Piperenol_A) hSGLT2 inhibitors were successfully identified, which were proven to exhibit excellent binding affinities, pharmacokinetic properties and less toxicity than the commercially available hSGLT2 inhibitor, canagliflozin, via molecular docking, ADMET prediction, molecular dynamics (MD) simulations and binding free energy calculations. All together, our results strongly suggest that these two compounds have great potential to serve as novel hSGLT2 inhibitors for the treatment of T2DM and their efficacies may be further examined by a series of in vitro and/or in vivo bioassays.
基金The project supported by the Research Special Fund for the National Great Science and Technology Projects(2012ZX09301002,2012ZX09508104,2013ZX09402203)the International Col aboration Project(2011DFR31240)Peking Union Medical College Graduate Student Innovation Fund(2013-1007-18)
文摘OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key targets toward Alzheimer disease.Then,druglikeness,oral bioavailability and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for central nervous system diseases treatment.Finallly,we were attempted to predict the targets of constituents and find potential multi-target compounds from Nao De Sheng formula by combining the advantages of machine learning,molecular docking and pharmacophore mapping together.RESULTS Constituenttarget network,constituent-target-target network and targetbiological pathway network were built to explain the network pharmacology of the constituents in NaoD eS heng formula.CONCLUSION To the best of our knowledge,we were the first to study the mechanism of Nao De Sheng formula for potential efficacy for Alzheimer disease treatment by means of the virtual screening and network pharmacology methods.
基金Supported by the Natural Science Foundation of Guangdong Province(No.2015A030311012)the Science and Technology Project of Guangzhou City(No.201607010215)
文摘Natural products are characterized with diverse structures and biological activities. They show a certain degree of adaptability to human beings. However, they need to be modified to increase their druggability. Several strategies including pharmacophore similarity, physicochemical property optimization, and bioactivity focus may help to make them more drug-like candidates.
基金National Science Foundation of China(Project No.81430094 and No.81603311)Beijing Municipal Natural Science Foundation(No.7164239).
文摘Objective:Explicating the property and action of traditional Chinese medicine(TCM)in the perspectives of modern science deepens the insight into the property of TCM,and provides the basis for new drug discovery and clinical therapy.In this study,we investigated the relationship between transient receptor potential melastatin 8(TRPM8)and pungent flavor using three-dimensional pharmacophores based on virtual screening methods.Methods:Firstly,an inhouse database was established to identify the related pharmacological action according to the traditional Chinese herbs expressing an action of promoting blood circulation.Then,several therapeutic targets,3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-CoAR),cholesteryl ester transfer protein(CETP),Niemann-Pick C1-Like 1(NPC1L1)and platelet-activating factor receptor(PAFR),were selected to screen traditional Chinese herbs,and the common virtual screening hits with various hit scores providing data to reveal the correlation among TRPM8 and therapeutic targets.Results:According to the screening results,TRPM8 agonists were able to identify the effective components of pungent herbs and TRPM8,which shares the common virtual screening hits with the therapeutic targets,was considered to be related to the action of pungent taste.Conclusion:The novel ideas and methods in this study are beneficial to unveil the scientific relationship between a TCM property and its action.
文摘Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.
文摘It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors by carrying out structural modifications and optimizations in future studies.
文摘A new class of potential antibacterial agents has been synthesized on a new molecular scaffold of cyclohexane carboxylate. We have tagged this new class of compounds TACCs (Trisubstituted Aryl Cyclohexanecarboxylate). These new molecules are structural analogues of an Activators of Self-Compartmentalizing Proteases 4 and 5 (ACP 4 and 5), and were synthesized to circumvent the drug-like property (drug-ability) challenges and liability noted in ACP 4 and 5. A pseudo-Robinson annulation protocol was used to furnish this new class of potential antibiotics. Structure-activity relationship (SAR) study was done to identify the pharmacophore(s) in this molecular scaffold. A selection of these compounds was used in our preliminary antibacterial inhibitory activities’ studies on Bacillus mycoides and Bacillus subtilis. These preliminary studies show that the TACCs exhibited equal, and in some cases better, antibacterial activity than ACP 4 and 5.