Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibi...Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.展开更多
Acetaldehyde dehydrogenase 1A1 is a hopeful therapeutic target to ovarian cancer. In this present work, 3D-QSAR, molecular docking and molecular dynamics(MD) simulations were implemented on a series of quinoline-based...Acetaldehyde dehydrogenase 1A1 is a hopeful therapeutic target to ovarian cancer. In this present work, 3D-QSAR, molecular docking and molecular dynamics(MD) simulations were implemented on a series of quinoline-based ALDH1A1 inhibitors to investigate novel acetaldehyde dehydrogenase 1A1 inhibitors as anticancer adjuvant drugs for ovarian cancer. Two reliable CoMFA(Q^(2) = 0.583, R^(2) = 0.967) and CoMSIA(Q^(2) = 0.640, R^(2) = 0.977) models of ALDH1A1 inhibitors were established. Novel ALDH1A1 inhibitors were predicted by the 3D-QSAR models. Molecular docking reveals important residues for protein-compound interactions, and the results revealed ALDH1A1 inhibitors had stronger electrostatic interaction and binding affinity with key residues of protein, such as Phe171, Val174 and Cys303. Molecular dynamics simulations further verified the results of molecular docking. The above information provided significant guidance for the design of novel ALDH1A1 inhibitors.展开更多
The molecular dynamics method is used to investigate decomposition of methane hydrate at different temperatures,pressures and concentrations of inhibitor.By analyzing the parameters of system conformation,mean square ...The molecular dynamics method is used to investigate decomposition of methane hydrate at different temperatures,pressures and concentrations of inhibitor.By analyzing the parameters of system conformation,mean square displacement and radial distribution function,the decomposition of hydrate in the presence of alcohol inhibitors ethylene glycol and glycerol is explored.The results show that the hydroxyl groups in alcohol molecules can destroy the cage structure of hydrate,and form hydrogen bonds with nearby water molecules to effectively prevent the reformation of hydrate.Therefore,ethylene glycol and glycerol serve as inhibitors of methane hydrate,furthermore,in terms of inhibition effect,glycerol is better than ethylene glycol by comparing rate of hydrate decomposition.展开更多
The p110α,catalytic subunit of PI3Ka,was the primary phosphoinositide 3-kinases(PI3Ks)isoform involved in oncogenic RTK signaling and tumorigenesis.In this study,the three-dimensional quantitative structure-activity ...The p110α,catalytic subunit of PI3Ka,was the primary phosphoinositide 3-kinases(PI3Ks)isoform involved in oncogenic RTK signaling and tumorigenesis.In this study,the three-dimensional quantitative structure-activity relationship(3D-QSAR),molecular docking and molecular dynamics simulation were employed to study the binding mode between 3-phenylsulfonylaminopyridine derivatives and PI3Kα.The stable and reliable 3D-QSAR models were constructed based on the application of the comparative molecular field analysis(CoMFA)model(q^(2)=0.704,r^(2)=0.994)and comparative molecular similarity index analysis(CoMSIA)model(q^(2)=0.804,r^(2)=0.996).The contour maps illustrated relationship between structure and biological activity.The conformation obtained after MD simulation was more stable than the docked conformation.MD simulation was performed in a more realistic environment,and was much closer to physiological conditions.As a result,five novel PI3Kα inhibitors were designed with better biological activity than the template compound 8.展开更多
Objective： To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 （EHD1 EH domain） with three peptides containing NPF ...Objective： To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 （EHD1 EH domain） with three peptides containing NPF （asparagine-proline-phenylalanine）, DPF （aspartic acid-proline-phenylalanine）, and GPF （glycine-proline-phenylalanine） motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated. Methods： Molecular dynamics （MD） simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/ generalized Born surface area （MM/GBSA） method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software. Results： The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the struc- tural basis of contributions of van der Waals interactions of the flanking residues to the binding. Conclusions： van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues.展开更多
Aldosterone synthase inhibitors can lessen the production of aldosterone in organisms,which effec-tively affecting the treatment of hypertension.A series of computational approaches like QSAR,docking,DFT and molecular...Aldosterone synthase inhibitors can lessen the production of aldosterone in organisms,which effec-tively affecting the treatment of hypertension.A series of computational approaches like QSAR,docking,DFT and molecular dynamics simulation are applied on 40 benzimidazole derivatives of aldosterone synthase(CYP11B2)in-hibitors.Statistical parameters:Q^(2)=0.877,R^(2)=0.983(CoMFA)and Q^(2)=0.848,R^(2)=0.994(CoMSIA)indicate on good predictive power of both models and DFT’s result illustrates the stability of both models.Besides,Y-randomization test is also performed to ensure the robustness of the obtained 3D-QSAR models.Docking studies show inhibitors rely onπ-πinteraction with residues,such as Phe130,Ala313 and Phe481.Molecular dynamics simulation results further confirm that the hydrophobic interaction with proteins enhances the inhibitor’s inhibitory effect.Based on QSAR studies and molecular docking,we designed novel compounds with enhanced activity against aldosterone synthase.Furthermore,the newly designed compounds are analyzed for their ADMET proper-ties and drug likeness and the results show that they all have excellent bioavailability.展开更多
CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, ...CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, blocking of CCR5 has been considered as an effective strategy in HIV-1/cancers therapy. So far, only Maraviroc has been approved by FDA in 2007, while the other CCR5 inhibitors have failed in their clinical trials. In this study, a highly selective structure-based pharmacophore model was constructed, validated, and applied for virtual screening to retrieve novel CCR5 inhibitors from NCI database. Finally, one potential CCR5 inhibitor candidate, NSC13165, was identified after molecular docking, molecular dynamics (MD) simulations, binding free energy analyses and ADMET prediction. Docking and MD simulation results not only suggested that NSC13165 reserves the common binding mode of the most known CCR5 inhibitors, but also provided important insights toward the allosteric inhibition mechanism of CCR5. The results of binding free energy analyses indicated that the binding affinity of NSC13165 is much better than that of Maraviroc and that van der Waals interaction is the key driving force during the binding process. ADMET prediction suggested that NSC13165 exhibits very low risk of causing lethal side effects. Altogether, our results strongly suggest that NSC13165 has great potential to serve as a novel CCR5 inhibitor, which may be further tested in vitro/in vivo as a drug target for HIV-1/cancers therapy or be used as a lead compound for improving its efficacy through chemical modifications.展开更多
目的采用药效团模型和分子对接方法对ZINC、Chembridge数据库进行虚拟筛选,并通过酶活性测试进行验证,以发现新骨架结构的IDO1抑制剂。方法通过分子对接方法靶向IDO1酶活性位点,对ZINC数据库进行虚拟筛选,得到苗头化合物,进行酶活性测试...目的采用药效团模型和分子对接方法对ZINC、Chembridge数据库进行虚拟筛选,并通过酶活性测试进行验证,以发现新骨架结构的IDO1抑制剂。方法通过分子对接方法靶向IDO1酶活性位点,对ZINC数据库进行虚拟筛选,得到苗头化合物,进行酶活性测试,发现酶活性较好的先导化合物;随后用已进入临床研究的3个IDO1抑制剂构建药效团模型,以此模型对先导化合物类似物进行虚拟筛选,并测定化合物的抑酶活性;通过分子动力学模拟探究化合物与IDO1的结合模式。结果通过分子对接方法对超过200万个虚拟化合物进行筛选得到11个先导化合物并测酶活性,其中ZINC91657208抑酶活性较好,IC50约为77.15μmol/L,活性骨架为4-羟基喹啉。亚结构检索4-羟基喹啉的结构得到31个类似物,利用药效团虚拟筛选出10个化合物,并测酶活性,其中3个4-羟基喹啉类化合物均具有明显的抑酶活性,而Chembridge29374490为酶活性最好的IDO1抑制剂,其IC50约为37.78μmol/L。经分子动力学模拟平衡后,其骨架原子均方差偏根(root mean square deviation, RMSD)分别为1?和2.4?。结论从ZINC和Chembridge数据库中发现了新型4-羟基喹啉类IDO1抑制剂。展开更多
HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibit...HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibitors （NNRTIs）. In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database （TCMD） using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 （a compound derived from TCMD） has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.展开更多
Protein-protein interactions are vital for a wide range of biological processes.The interactions between the hypoxia-inducible factor and von Hippel Lindau(VHL)are attractive drug targets for ischemic heart disease.In...Protein-protein interactions are vital for a wide range of biological processes.The interactions between the hypoxia-inducible factor and von Hippel Lindau(VHL)are attractive drug targets for ischemic heart disease.In order to disrupt this interaction,the strategy to target VHL binding site using a hydroxyproline-like(pro-like)small molecule has been reported.In this study,we focused on the inhibition mechanism between the pro-like inhibitors and the VHL protein,which were investigated via molecular dynamics simulations and binding free energy calculations.It was found that pro-like inhibitors showed a strong binding affinity toward VHL.Binding free energy calculations and free energy decompositions suggested that the modification of various regions of pro-like inhibitors may provide useful information for future drug design.展开更多
Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary appr...Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be ac- cessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of bind- ing and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APAfrom HIV-1 reverse transcriptase.展开更多
文摘Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.
基金supported by the key project of Chongqing natural science foundation(cstc2015jcyjBX0080)。
文摘Acetaldehyde dehydrogenase 1A1 is a hopeful therapeutic target to ovarian cancer. In this present work, 3D-QSAR, molecular docking and molecular dynamics(MD) simulations were implemented on a series of quinoline-based ALDH1A1 inhibitors to investigate novel acetaldehyde dehydrogenase 1A1 inhibitors as anticancer adjuvant drugs for ovarian cancer. Two reliable CoMFA(Q^(2) = 0.583, R^(2) = 0.967) and CoMSIA(Q^(2) = 0.640, R^(2) = 0.977) models of ALDH1A1 inhibitors were established. Novel ALDH1A1 inhibitors were predicted by the 3D-QSAR models. Molecular docking reveals important residues for protein-compound interactions, and the results revealed ALDH1A1 inhibitors had stronger electrostatic interaction and binding affinity with key residues of protein, such as Phe171, Val174 and Cys303. Molecular dynamics simulations further verified the results of molecular docking. The above information provided significant guidance for the design of novel ALDH1A1 inhibitors.
基金Sponsored by the National Natural Science Foundation of China(Grant No.51876032)the Natural Science Foundation of Heilongjiang Province of China(Grant No.ZD2019E002).
文摘The molecular dynamics method is used to investigate decomposition of methane hydrate at different temperatures,pressures and concentrations of inhibitor.By analyzing the parameters of system conformation,mean square displacement and radial distribution function,the decomposition of hydrate in the presence of alcohol inhibitors ethylene glycol and glycerol is explored.The results show that the hydroxyl groups in alcohol molecules can destroy the cage structure of hydrate,and form hydrogen bonds with nearby water molecules to effectively prevent the reformation of hydrate.Therefore,ethylene glycol and glycerol serve as inhibitors of methane hydrate,furthermore,in terms of inhibition effect,glycerol is better than ethylene glycol by comparing rate of hydrate decomposition.
文摘The p110α,catalytic subunit of PI3Ka,was the primary phosphoinositide 3-kinases(PI3Ks)isoform involved in oncogenic RTK signaling and tumorigenesis.In this study,the three-dimensional quantitative structure-activity relationship(3D-QSAR),molecular docking and molecular dynamics simulation were employed to study the binding mode between 3-phenylsulfonylaminopyridine derivatives and PI3Kα.The stable and reliable 3D-QSAR models were constructed based on the application of the comparative molecular field analysis(CoMFA)model(q^(2)=0.704,r^(2)=0.994)and comparative molecular similarity index analysis(CoMSIA)model(q^(2)=0.804,r^(2)=0.996).The contour maps illustrated relationship between structure and biological activity.The conformation obtained after MD simulation was more stable than the docked conformation.MD simulation was performed in a more realistic environment,and was much closer to physiological conditions.As a result,five novel PI3Kα inhibitors were designed with better biological activity than the template compound 8.
基金supported by the National Natural Science Foundation of China(Nos.11172259 and 31471807)the Special Fund for Agro-scientific Research in the Public Interest(No.201403030),China
文摘Objective： To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 （EHD1 EH domain） with three peptides containing NPF （asparagine-proline-phenylalanine）, DPF （aspartic acid-proline-phenylalanine）, and GPF （glycine-proline-phenylalanine） motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated. Methods： Molecular dynamics （MD） simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/ generalized Born surface area （MM/GBSA） method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software. Results： The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the struc- tural basis of contributions of van der Waals interactions of the flanking residues to the binding. Conclusions： van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues.
基金supported by the graduate student innovation project of Chongqing University of Technology (clgycx 20202129)
文摘Aldosterone synthase inhibitors can lessen the production of aldosterone in organisms,which effec-tively affecting the treatment of hypertension.A series of computational approaches like QSAR,docking,DFT and molecular dynamics simulation are applied on 40 benzimidazole derivatives of aldosterone synthase(CYP11B2)in-hibitors.Statistical parameters:Q^(2)=0.877,R^(2)=0.983(CoMFA)and Q^(2)=0.848,R^(2)=0.994(CoMSIA)indicate on good predictive power of both models and DFT’s result illustrates the stability of both models.Besides,Y-randomization test is also performed to ensure the robustness of the obtained 3D-QSAR models.Docking studies show inhibitors rely onπ-πinteraction with residues,such as Phe130,Ala313 and Phe481.Molecular dynamics simulation results further confirm that the hydrophobic interaction with proteins enhances the inhibitor’s inhibitory effect.Based on QSAR studies and molecular docking,we designed novel compounds with enhanced activity against aldosterone synthase.Furthermore,the newly designed compounds are analyzed for their ADMET proper-ties and drug likeness and the results show that they all have excellent bioavailability.
文摘CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, blocking of CCR5 has been considered as an effective strategy in HIV-1/cancers therapy. So far, only Maraviroc has been approved by FDA in 2007, while the other CCR5 inhibitors have failed in their clinical trials. In this study, a highly selective structure-based pharmacophore model was constructed, validated, and applied for virtual screening to retrieve novel CCR5 inhibitors from NCI database. Finally, one potential CCR5 inhibitor candidate, NSC13165, was identified after molecular docking, molecular dynamics (MD) simulations, binding free energy analyses and ADMET prediction. Docking and MD simulation results not only suggested that NSC13165 reserves the common binding mode of the most known CCR5 inhibitors, but also provided important insights toward the allosteric inhibition mechanism of CCR5. The results of binding free energy analyses indicated that the binding affinity of NSC13165 is much better than that of Maraviroc and that van der Waals interaction is the key driving force during the binding process. ADMET prediction suggested that NSC13165 exhibits very low risk of causing lethal side effects. Altogether, our results strongly suggest that NSC13165 has great potential to serve as a novel CCR5 inhibitor, which may be further tested in vitro/in vivo as a drug target for HIV-1/cancers therapy or be used as a lead compound for improving its efficacy through chemical modifications.
基金supported by grants from The National Natural Science Foundation of China(30670497)National Basic Research Program of China(2009CB930200)+1 种基金Beijing Natural Science Foundation(5072002,7082006)Research Fund for the Doctorate Program(X0015001200801)~~
文摘目的采用药效团模型和分子对接方法对ZINC、Chembridge数据库进行虚拟筛选,并通过酶活性测试进行验证,以发现新骨架结构的IDO1抑制剂。方法通过分子对接方法靶向IDO1酶活性位点,对ZINC数据库进行虚拟筛选,得到苗头化合物,进行酶活性测试,发现酶活性较好的先导化合物;随后用已进入临床研究的3个IDO1抑制剂构建药效团模型,以此模型对先导化合物类似物进行虚拟筛选,并测定化合物的抑酶活性;通过分子动力学模拟探究化合物与IDO1的结合模式。结果通过分子对接方法对超过200万个虚拟化合物进行筛选得到11个先导化合物并测酶活性,其中ZINC91657208抑酶活性较好,IC50约为77.15μmol/L,活性骨架为4-羟基喹啉。亚结构检索4-羟基喹啉的结构得到31个类似物,利用药效团虚拟筛选出10个化合物,并测酶活性,其中3个4-羟基喹啉类化合物均具有明显的抑酶活性,而Chembridge29374490为酶活性最好的IDO1抑制剂,其IC50约为37.78μmol/L。经分子动力学模拟平衡后,其骨架原子均方差偏根(root mean square deviation, RMSD)分别为1?和2.4?。结论从ZINC和Chembridge数据库中发现了新型4-羟基喹啉类IDO1抑制剂。
基金supported by the grants from Chinese National Science Foundation(No.30472166)the Tianjin Commission of Sciences and Technology under the Contract(No.06YFGZSH07000)
文摘HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibitors （NNRTIs）. In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database （TCMD） using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 （a compound derived from TCMD） has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.
基金supported by the National Natural Science Foundation of China(No.21973064)the Post-Doctor Research Project,West China Hospital,Sichuan University(No.2021HXBH017)。
文摘Protein-protein interactions are vital for a wide range of biological processes.The interactions between the hypoxia-inducible factor and von Hippel Lindau(VHL)are attractive drug targets for ischemic heart disease.In order to disrupt this interaction,the strategy to target VHL binding site using a hydroxyproline-like(pro-like)small molecule has been reported.In this study,we focused on the inhibition mechanism between the pro-like inhibitors and the VHL protein,which were investigated via molecular dynamics simulations and binding free energy calculations.It was found that pro-like inhibitors showed a strong binding affinity toward VHL.Binding free energy calculations and free energy decompositions suggested that the modification of various regions of pro-like inhibitors may provide useful information for future drug design.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.20102007,29725203 and 20072042)the State Key Program of Basic Research of China(Grant No.2002CB512802)+1 种基金the 863 Hi-Tech Program of China(Grant Nos.2002AA233011,2002AA233061,2001AA235051 and 2001AA 235041)Foundation of Shanghai Ministry of Science and Technology,and the Key Program of New Drug Research and Development from the Chinese Academy of Sciences.
文摘Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be ac- cessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of bind- ing and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APAfrom HIV-1 reverse transcriptase.
