The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase (IN), which includes two important reactions, 3'-processing and strand transfer, both catalyzed by HIV-1 IN. Disr...The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase (IN), which includes two important reactions, 3'-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors (INSTIs). Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2+ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.展开更多
Capsid protein enterovirus 71 (EV71) is one of the major viruses that cause the severe encephalitis and thus result in a high mortality in children less than 5 years of age.In an effort to discover new potent inhibi...Capsid protein enterovirus 71 (EV71) is one of the major viruses that cause the severe encephalitis and thus result in a high mortality in children less than 5 years of age.In an effort to discover new potent inhibitors against EV71,a novel three-dimensional pharmacophore model was developed on 24 inhibitors with different molecular structures and bioactivities.The best hypothesis (Hypo1) has a high predictive power and consists of four features,namely,one hydrophobic point (HY) and three hydrogen-bond acceptors (HA).Two key features of the best Hypo1,HY1 and HA3 match well with an important narrow hydrophobic canyon and with the surface of LYS274 in the target EV71 active site,respectively.The more versatile feature,HA1,is firstly found to be very influential on these compounds’ bioactivities,which may interact with the other side of the active site in the EV71 receptor.The application of the model is successful in predicting the activities of 30 known EV71 inhibitors with a correlation coefficient of 0.831.Furthermore,Hypo1 demonstrates a superior screening capability for retrieving inhibitors from the database with a high enrichment factor of 70.This study provides some important clues in search for more potent inhibitors against EV71 infection.展开更多
In the present study we investigated two groups of small molecular tyrosine kinase phosphorylation inhibitors (tyrphostins) with quite different structures (19 compounds of the benzylidene malononitrile famliy and 13 ...In the present study we investigated two groups of small molecular tyrosine kinase phosphorylation inhibitors (tyrphostins) with quite different structures (19 compounds of the benzylidene 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-dimensional pharmacophore model to these two kinds of molecules has been discovered. A better 3D-QSAR analysis based on the generated pharmacophore model was conducted (correlate coeffcient R=0.956) and the model shows very good predictive ability.展开更多
Objective To screen the active compounds in Sini Decoction showing the potential to inhibit tumor necrosis factor α(TNFα) to alleviate Doxorubicin(DOX)-induced heart failure. Methods A chemical database of Sini ...Objective To screen the active compounds in Sini Decoction showing the potential to inhibit tumor necrosis factor α(TNFα) to alleviate Doxorubicin(DOX)-induced heart failure. Methods A chemical database of Sini Decoction was constructed from literature research. The generated pharmacophore models based on TNF-α used to screen active ingredients of Sini Decoction in the database by Discovery Studio 2.5. Molecular docking by Autodock 4.2 was adopted to demonstrate the hit compounds' affinities with TNFα. Furthermore, DOX-induced heart failure model on H9c2 cell line was constructed and cell viability was detected by CCK-8 to validate the therapeutic effect of potential active compounds. Results The higenamine showed potential cardiovascular protective effect through virtual screening. And the activity was identified in vitro. Conclusion In this study, we found that higenamine may inhibit TNF-ɑ through virtual docking and validated that higenamine may have the potential of treatment for heart failure in the model of doxorubicin-induced myocardial toxicity to H9c2 cells.展开更多
BACKGROUND: P-glycoprotein (P-gp) is a 170-kDa membrane protein. It provides a barrier function and help to excrete toxins from the body as a transporter. Some bioflavonoids have been shown to block P-gp activity. ...BACKGROUND: P-glycoprotein (P-gp) is a 170-kDa membrane protein. It provides a barrier function and help to excrete toxins from the body as a transporter. Some bioflavonoids have been shown to block P-gp activity. OBJECTIVE: To evaluate the important amino acid residues within nucleotide binding domain 1 (NBD l) of P-gp that play a key role in molecular interactions with flavonoids using structure-based pharmacophore model. METHODS: In the molecular docking with NBD 1 models, a putative binding site of flavonoids was proposed and compared with the site for ATP. The binding modes for ligands were achieved using LigandScout to generate the P-gp-flavonoid pharmacophore models. RESULTS: The binding pocket for flavonoids was investigated and found these inhibitors compete with the ATP for binding site in NBD1 including the NBD1 amino acid residues identified by the in silico techniques to be involved in the hydrogen bonding and van der Waals (hydrophobic) interactions with flavonoids. CONCLUSION: These flavonoids occupy with the same binding site of ATP in NBD1 proffering that they may act as an ATP competitive inhibitor.展开更多
The serotonin 2A(5-HT2A) receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression.In this study,a poten...The serotonin 2A(5-HT2A) receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression.In this study,a potent novel 5-HT2A inhibitor 05245768 with a Ki value of (593.89±34.10) nmol/L was discovered by integrating a set of computational approaches and experiments(protein structure prediction,pharmacophore-based virtual screening,automated molecular docking and pharmacological bioassay).The 5-HT2A receptor showed a negatively charged bin-ding pocket.The binding mode of compound 05245768 with 5-HT2A was obtained by GOLD docking procedure,which revealed the conserved interaction between protonated nitrogen in compound 05245768 and carboxylate group of D3.32 at the active site of 5-HT2A.展开更多
<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
The aberrant overexpression of cyclin-dependent kinase 9 (CDK9) in cancer cells results in the loss of proliferative control, making it an attractive therapeutic target for various cancers. However, the highly structu...The aberrant overexpression of cyclin-dependent kinase 9 (CDK9) in cancer cells results in the loss of proliferative control, making it an attractive therapeutic target for various cancers. However, the highly structural similarity between CDK9 and CDK2 makes the development of novel selective CDK9 inhibitors a challenging task and thus limits their clinical applications. Here, an effective two-stage virtual screening strategy was developed to identify novel CDK9 inhibitors with better inhibitory activity and higher selectivity. The first screening stage aims to select potential compounds with better inhibitory activity than Roniciclib, one of the most effective CDK9 inhibitors, through reliable structure-based pharmacophoric virtual screening and accurate molecular docking analyses. The second stage employs a very detailed visual inspection process, in which several structural criteria describing the major difference between the binding pockets of CDK9 and CDK2 are taken into consideration, to identify compounds with higher selectivity than CAN508, one of the CDK9 inhibitors with distinguished selectivity. Finally, three compounds (NCI207113 from NCI database and TCM0004 and TCM3282 from TCM database) with better inhibitory activity and higher selectivity were successfully identified as novel CDK9 inhibitors. These three compounds also display excellent binding stabilities, great pharmacokinetic properties and low toxicity in MD simulations and ADMET predictions. Besides, the results of binding free energy calculations suggest that enhancing van der Waals interaction and nonpolar solvation energy and/or reducing polar solvation energy can significantly improve the binding affinity of these CDK9 inhibitors. Their clinical potentials to serve as anticancer drug candidates can be further evaluated through a series of <em>in vitro/in vivo</em> bioassays in the future. To the best of our knowledge, this is the first attempt to identify novel CDK9 inhibitors with both better inhibitory activity and higher selectivity through an effective two-stage virtual screening strategy.展开更多
3-Arylisothiazolo[5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo[5,4-b]quinolin-4(9H)-ones were synthesized and assayed for affinity for the benzodiazepine binding site of the GABAA receptors. While the 3-arylisothiazo...3-Arylisothiazolo[5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo[5,4-b]quinolin-4(9H)-ones were synthesized and assayed for affinity for the benzodiazepine binding site of the GABAA receptors. While the 3-arylisothiazoloquinolin-4-ones were found to be potent ligands, with affinities (expressed as the affinity Ki value) down to 1 nM, the 3-arylisoxazoloquinolin-4-ones are less potent. This is suggested to depend on sterical repulsive interaction of the 3-arylisoxazoloquinolin-4-ones with the receptor essential volume of the binding site, and a higher electron density at the nitrogen in the azole ring (N-2) as well as the carbonyl oxygen in the isothiazoloquinolin-4-ones enabling them to interact stronger with hydrogen bond donor sites at the binding site.展开更多
Neuraminidase is a significant anti-influenza target that plays crucial role in virus replication cycle. The discov- ery of 150-cavity in Group-1 neuraminidase provides us a novel mentality of designing inhibitor whic...Neuraminidase is a significant anti-influenza target that plays crucial role in virus replication cycle. The discov- ery of 150-cavity in Group-1 neuraminidase provides us a novel mentality of designing inhibitor which can bind with both conserved site and 150-cavity. In order to discover novel dual-site-binding inhibitors, a 3D chemi- cal-feature-based pharmacophore model was established to cover dual-site in neuraminidase. The dual-site-binding model was consistent in predicting the binding conformation of Group-1 neuraminidase inhibitor and applied for virtual screening of Specs database. Compound 4 (ZINC05790048) that aligned well to the model was selected after multiple filtrations for molecular dynamics simulations, indicating improved binding energy with neuraminidase. It can sever as the lead compound for a novel series of inhibitors.展开更多
28 kinds of carotenoids are studied to reveal the key parameters and regulation on the singlet oxygen quenching rate.First,the quantum chemistry parameters of carotenoids calculated by Gaussian software combined with ...28 kinds of carotenoids are studied to reveal the key parameters and regulation on the singlet oxygen quenching rate.First,the quantum chemistry parameters of carotenoids calculated by Gaussian software combined with substitution parameters were used to construct the quantitative structure-activity relationship model(QSAR)of the singlet oxygen quenching rate of carotenoids.The key parameters affecting the antioxidant activity of carotenoids are revealed,and the data predicted via the QSAR model were provided for subsequent research.Then,a three-dimensional(3D)pharmacophore model was used to regulate and modify the antioxidant activity of carotenoids.The correlation coefficients of the modeling group(R2)and verification group(Rpre2)of the established QSAR model were 0.945 and 0.916,respectively,which can be used for the analysis of antioxidant activity of carotenoids;the antioxidant activity of carotenoids can be significantly regulated by the number of conjugated C=C bonds,the energy difference between frontier molecular orbitals and the partial Mulliken charge in C1 and theπ···π*excitation energy E(s);the antioxidant activity of carotenoids can be effectively regulated by the hydrogen bond acceptor pharmacophores on both sides of the conjugated C=C bonds and the hydrophobic groups on the conjugated C=C bond;the hydrophobic substituents attached to conjugated C=C bonds can effectively improve the singlet oxygen quenching rate of carotenoids.展开更多
Chiral drug naftopidil(NAF), a specific α1D-adrenoceptor(AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers s...Chiral drug naftopidil(NAF), a specific α1D-adrenoceptor(AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α1D-selective antagonists. Based on the constructed α1D homology model,molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.展开更多
Matrix metalloproteinase-13(MMP-13) has been considered as a promising therapeutic target for osteoarthritis. In this work, the experimental crystal structures of five MMP-13-ligand complexes are used to build the mul...Matrix metalloproteinase-13(MMP-13) has been considered as a promising therapeutic target for osteoarthritis. In this work, the experimental crystal structures of five MMP-13-ligand complexes are used to build the multiple structure-based pharmacophore model of MMP-13 inhibitors. The reliability of pharmacophore model is validated using a decoy set. The pharmacophore model contains four chemical features: two hydrogen bond acceptor(HBA), one hydrophobic(HY) feature, and one ring aromatic(RA) feature. Particularly, the HY feature is found to orient the MMP-13 inhibitors deep into the S1’ pocket of MMP-13 to produce selective inhibition. By carrying out the screening of pharmacophore model and subsequent molecular docking, the four non-zinc-chelating selective MMP-13 inhibitors of natural products(NP-015973, NP-000814, STOCK1 N-24933, and STOCK1 N-69443) are identified. It is found that the binding modes of MMP-13 with our screened four natural products are very similar to the reported experimental binding mode of MMP-13 with the most active inhibitor(GG12003, IC50: 0.67 n M), and each of them involves the interactions of a ligand with the three amino acid residues Thr226, Lys119, and His201 of MMP-13 receptor. This shows that our modeling results are in good agreement with the relevant experimental results, which strongly supports our screened MMP-13 inhibitors of natural products. These screened natural products may be used as the lead compounds of MMP-13 inhibitors in the future studies of structural modifications.展开更多
基金supported by the National Natural Science Foundation of China (No. 30472166)the Tianjin Commission of Science and Technology (06YFGZSH07000)
文摘The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase (IN), which includes two important reactions, 3'-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors (INSTIs). Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2+ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.
基金Sponsored by the National Natural Science Foundation of China (No. 30800719)
文摘Capsid protein enterovirus 71 (EV71) is one of the major viruses that cause the severe encephalitis and thus result in a high mortality in children less than 5 years of age.In an effort to discover new potent inhibitors against EV71,a novel three-dimensional pharmacophore model was developed on 24 inhibitors with different molecular structures and bioactivities.The best hypothesis (Hypo1) has a high predictive power and consists of four features,namely,one hydrophobic point (HY) and three hydrogen-bond acceptors (HA).Two key features of the best Hypo1,HY1 and HA3 match well with an important narrow hydrophobic canyon and with the surface of LYS274 in the target EV71 active site,respectively.The more versatile feature,HA1,is firstly found to be very influential on these compounds’ bioactivities,which may interact with the other side of the active site in the EV71 receptor.The application of the model is successful in predicting the activities of 30 known EV71 inhibitors with a correlation coefficient of 0.831.Furthermore,Hypo1 demonstrates a superior screening capability for retrieving inhibitors from the database with a high enrichment factor of 70.This study provides some important clues in search for more potent inhibitors against EV71 infection.
文摘In the present study we investigated two groups of small molecular tyrosine kinase phosphorylation inhibitors (tyrphostins) with quite different structures (19 compounds of the benzylidene 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-dimensional pharmacophore model to these two kinds of molecules has been discovered. A better 3D-QSAR analysis based on the generated pharmacophore model was conducted (correlate coeffcient R=0.956) and the model shows very good predictive ability.
基金National Natural Science Foundation of China(No.81273472)
文摘Objective To screen the active compounds in Sini Decoction showing the potential to inhibit tumor necrosis factor α(TNFα) to alleviate Doxorubicin(DOX)-induced heart failure. Methods A chemical database of Sini Decoction was constructed from literature research. The generated pharmacophore models based on TNF-α used to screen active ingredients of Sini Decoction in the database by Discovery Studio 2.5. Molecular docking by Autodock 4.2 was adopted to demonstrate the hit compounds' affinities with TNFα. Furthermore, DOX-induced heart failure model on H9c2 cell line was constructed and cell viability was detected by CCK-8 to validate the therapeutic effect of potential active compounds. Results The higenamine showed potential cardiovascular protective effect through virtual screening. And the activity was identified in vitro. Conclusion In this study, we found that higenamine may inhibit TNF-ɑ through virtual docking and validated that higenamine may have the potential of treatment for heart failure in the model of doxorubicin-induced myocardial toxicity to H9c2 cells.
文摘BACKGROUND: P-glycoprotein (P-gp) is a 170-kDa membrane protein. It provides a barrier function and help to excrete toxins from the body as a transporter. Some bioflavonoids have been shown to block P-gp activity. OBJECTIVE: To evaluate the important amino acid residues within nucleotide binding domain 1 (NBD l) of P-gp that play a key role in molecular interactions with flavonoids using structure-based pharmacophore model. METHODS: In the molecular docking with NBD 1 models, a putative binding site of flavonoids was proposed and compared with the site for ATP. The binding modes for ligands were achieved using LigandScout to generate the P-gp-flavonoid pharmacophore models. RESULTS: The binding pocket for flavonoids was investigated and found these inhibitors compete with the ATP for binding site in NBD1 including the NBD1 amino acid residues identified by the in silico techniques to be involved in the hydrogen bonding and van der Waals (hydrophobic) interactions with flavonoids. CONCLUSION: These flavonoids occupy with the same binding site of ATP in NBD1 proffering that they may act as an ATP competitive inhibitor.
基金Supported by the National High Technology Research and Development Program of China(No.2009AA02Z308)the Major State Basic Research Development Program of China(No.2010CB912601)the National Natural Science Foundation of China (No.20702009)
文摘The serotonin 2A(5-HT2A) receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression.In this study,a potent novel 5-HT2A inhibitor 05245768 with a Ki value of (593.89±34.10) nmol/L was discovered by integrating a set of computational approaches and experiments(protein structure prediction,pharmacophore-based virtual screening,automated molecular docking and pharmacological bioassay).The 5-HT2A receptor showed a negatively charged bin-ding pocket.The binding mode of compound 05245768 with 5-HT2A was obtained by GOLD docking procedure,which revealed the conserved interaction between protonated nitrogen in compound 05245768 and carboxylate group of D3.32 at the active site of 5-HT2A.
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>
文摘The aberrant overexpression of cyclin-dependent kinase 9 (CDK9) in cancer cells results in the loss of proliferative control, making it an attractive therapeutic target for various cancers. However, the highly structural similarity between CDK9 and CDK2 makes the development of novel selective CDK9 inhibitors a challenging task and thus limits their clinical applications. Here, an effective two-stage virtual screening strategy was developed to identify novel CDK9 inhibitors with better inhibitory activity and higher selectivity. The first screening stage aims to select potential compounds with better inhibitory activity than Roniciclib, one of the most effective CDK9 inhibitors, through reliable structure-based pharmacophoric virtual screening and accurate molecular docking analyses. The second stage employs a very detailed visual inspection process, in which several structural criteria describing the major difference between the binding pockets of CDK9 and CDK2 are taken into consideration, to identify compounds with higher selectivity than CAN508, one of the CDK9 inhibitors with distinguished selectivity. Finally, three compounds (NCI207113 from NCI database and TCM0004 and TCM3282 from TCM database) with better inhibitory activity and higher selectivity were successfully identified as novel CDK9 inhibitors. These three compounds also display excellent binding stabilities, great pharmacokinetic properties and low toxicity in MD simulations and ADMET predictions. Besides, the results of binding free energy calculations suggest that enhancing van der Waals interaction and nonpolar solvation energy and/or reducing polar solvation energy can significantly improve the binding affinity of these CDK9 inhibitors. Their clinical potentials to serve as anticancer drug candidates can be further evaluated through a series of <em>in vitro/in vivo</em> bioassays in the future. To the best of our knowledge, this is the first attempt to identify novel CDK9 inhibitors with both better inhibitory activity and higher selectivity through an effective two-stage virtual screening strategy.
基金Financial support from the Swedish Board for Scientific Research(VR),the Knut and Alice Wallenberg Foundation,the Research School for Pharmaceutical Sciences at Lund University,Carlsberg Foundation,Denmark,and the NeuroScience PharmaBiotec Research Center,Den-mark,is gratefully acknowledged.
文摘3-Arylisothiazolo[5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo[5,4-b]quinolin-4(9H)-ones were synthesized and assayed for affinity for the benzodiazepine binding site of the GABAA receptors. While the 3-arylisothiazoloquinolin-4-ones were found to be potent ligands, with affinities (expressed as the affinity Ki value) down to 1 nM, the 3-arylisoxazoloquinolin-4-ones are less potent. This is suggested to depend on sterical repulsive interaction of the 3-arylisoxazoloquinolin-4-ones with the receptor essential volume of the binding site, and a higher electron density at the nitrogen in the azole ring (N-2) as well as the carbonyl oxygen in the isothiazoloquinolin-4-ones enabling them to interact stronger with hydrogen bond donor sites at the binding site.
文摘Neuraminidase is a significant anti-influenza target that plays crucial role in virus replication cycle. The discov- ery of 150-cavity in Group-1 neuraminidase provides us a novel mentality of designing inhibitor which can bind with both conserved site and 150-cavity. In order to discover novel dual-site-binding inhibitors, a 3D chemi- cal-feature-based pharmacophore model was established to cover dual-site in neuraminidase. The dual-site-binding model was consistent in predicting the binding conformation of Group-1 neuraminidase inhibitor and applied for virtual screening of Specs database. Compound 4 (ZINC05790048) that aligned well to the model was selected after multiple filtrations for molecular dynamics simulations, indicating improved binding energy with neuraminidase. It can sever as the lead compound for a novel series of inhibitors.
文摘28 kinds of carotenoids are studied to reveal the key parameters and regulation on the singlet oxygen quenching rate.First,the quantum chemistry parameters of carotenoids calculated by Gaussian software combined with substitution parameters were used to construct the quantitative structure-activity relationship model(QSAR)of the singlet oxygen quenching rate of carotenoids.The key parameters affecting the antioxidant activity of carotenoids are revealed,and the data predicted via the QSAR model were provided for subsequent research.Then,a three-dimensional(3D)pharmacophore model was used to regulate and modify the antioxidant activity of carotenoids.The correlation coefficients of the modeling group(R2)and verification group(Rpre2)of the established QSAR model were 0.945 and 0.916,respectively,which can be used for the analysis of antioxidant activity of carotenoids;the antioxidant activity of carotenoids can be significantly regulated by the number of conjugated C=C bonds,the energy difference between frontier molecular orbitals and the partial Mulliken charge in C1 and theπ···π*excitation energy E(s);the antioxidant activity of carotenoids can be effectively regulated by the hydrogen bond acceptor pharmacophores on both sides of the conjugated C=C bonds and the hydrophobic groups on the conjugated C=C bond;the hydrophobic substituents attached to conjugated C=C bonds can effectively improve the singlet oxygen quenching rate of carotenoids.
基金supported by grants from the National Science Foundation of Guangdong Province (No. S2013040014088)the Postdoctoral Science Foundation of Guangzhou City (Q188)partially supported by the Guangdong Major Scientific and Technological Special Project for New Drug Development (2013A022100029)
文摘Chiral drug naftopidil(NAF), a specific α1D-adrenoceptor(AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α1D-selective antagonists. Based on the constructed α1D homology model,molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.
文摘Matrix metalloproteinase-13(MMP-13) has been considered as a promising therapeutic target for osteoarthritis. In this work, the experimental crystal structures of five MMP-13-ligand complexes are used to build the multiple structure-based pharmacophore model of MMP-13 inhibitors. The reliability of pharmacophore model is validated using a decoy set. The pharmacophore model contains four chemical features: two hydrogen bond acceptor(HBA), one hydrophobic(HY) feature, and one ring aromatic(RA) feature. Particularly, the HY feature is found to orient the MMP-13 inhibitors deep into the S1’ pocket of MMP-13 to produce selective inhibition. By carrying out the screening of pharmacophore model and subsequent molecular docking, the four non-zinc-chelating selective MMP-13 inhibitors of natural products(NP-015973, NP-000814, STOCK1 N-24933, and STOCK1 N-69443) are identified. It is found that the binding modes of MMP-13 with our screened four natural products are very similar to the reported experimental binding mode of MMP-13 with the most active inhibitor(GG12003, IC50: 0.67 n M), and each of them involves the interactions of a ligand with the three amino acid residues Thr226, Lys119, and His201 of MMP-13 receptor. This shows that our modeling results are in good agreement with the relevant experimental results, which strongly supports our screened MMP-13 inhibitors of natural products. These screened natural products may be used as the lead compounds of MMP-13 inhibitors in the future studies of structural modifications.