Acquired Immunodeficiency Syndrome(AIDS) is a significant human health threat around the world. Therefore, the study of anti-human immunodeficiency virus(HIV) drug design has become an important task for today’s soci...Acquired Immunodeficiency Syndrome(AIDS) is a significant human health threat around the world. Therefore, the study of anti-human immunodeficiency virus(HIV) drug design has become an important task for today’s society. In this paper, a three-dimensional quantitative structure-activity relationships study(3 D-QSAR) was conducted on 53 HIV-1 integrase inhibitors(IN) using random sampling analysis on molecular surface(RASMS) and Topomer comparative molecular field analysis(Topomer CoMFA). The multiple correlation coefficients of fitting, cross-validation, and external validation of two models were 0.926, 0.815 and 0.908 and 0.930, 0.726 and 0.855, respectively. The results indicated that two models obtained had both favorable estimation stability and good prediction capability. Topomer Search was used to search appropriate R groups from ZINC database, and 28 new compounds were designed thereby. The Topomer CoMFA model was subsequently used to predict the biological activity of these compounds, showing that 24 of the new compounds were more active than the template molecule. Ligands of the template molecule and new designed compounds were used for molecular docking to study the interaction of these compounds with the protein receptor. The results show that the ligands would form hydrogen-bonding interactions with the residues LEU58, THR83, GLN62, MET155, LYS119 and ALA154 of the protein receptor generally, thereby providing additional insights for the design of even more effective HIV/AIDS drugs.展开更多
Peptides are one of the indispensable substances in life. The use of computer aided drug design(CADD) methods to design peptides and peptiodmimetics can short the design cycle, save research funding, improve the level...Peptides are one of the indispensable substances in life. The use of computer aided drug design(CADD) methods to design peptides and peptiodmimetics can short the design cycle, save research funding, improve the level of whole research to a large extent and guide the discovery of new drugs. In this paper, Melittin and amoebapore three-dimensional quantitative structureactivity relationship(3D-QSAR) models were established by using comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) method. The result shows that, the correlation coefficient(q^2) was 0.583 and non-cross-validation correlation coefficient(r^2) was 0.972 for the melittin CoMFA model. The q^2 and r^2 were 0.630 and 0.995 for the best CoMSIA model, 0.645 and 0.993 for the amoebapore CoMFA model, and 0.738 and 0.996 for the best CoMSIA model. The statistical parameters demonstrated that the CoMFA and CoMSIA models had both good predictive ability and high statistical stability, and can provide theoretical basis for designing new high activity polypeptide drugs.展开更多
硫代氨基甲酸酯（TCS）被确认为一种新的非核苷类HIV-1逆转录酶抑制剂。本文采用基于R基团搜索技术的Topomer Co MFA方法。实验一对111个硫代氨基甲酸酯衍生物分子进行了三维定量构效关系分析,得到3D-QSAR模型的q^2为0.616,r^2为0.751,...硫代氨基甲酸酯（TCS）被确认为一种新的非核苷类HIV-1逆转录酶抑制剂。本文采用基于R基团搜索技术的Topomer Co MFA方法。实验一对111个硫代氨基甲酸酯衍生物分子进行了三维定量构效关系分析,得到3D-QSAR模型的q^2为0.616,r^2为0.751,实验二对前60个分子进行同样的分析,得到q^2为0.777,r^2为0.913。两次实验结果表明所建立的模型在统计上都有较好的稳定性和预测能力,但相比之下,实验二更有利于抗艾滋病药物的设计。展开更多
In this paper, a three-dimensional quantitative structure-activity relationships(3 D-QSAR) study for 20 HIV-1 reverse transcriptase(RT) inhibitors was established using Topomer Co MFA. The models were built based on d...In this paper, a three-dimensional quantitative structure-activity relationships(3 D-QSAR) study for 20 HIV-1 reverse transcriptase(RT) inhibitors was established using Topomer Co MFA. The models were built based on different fragment cutting models, with the most effective model of the multiple correlation coefficients of fitting(r^2) to be 0.920, cross-validation(q^2) of 0.575, and external validation(Q_(ext)~2) being 0.701. The results indicated that the model obtained has both favorable estimation stability and good prediction capability. Topomer Search was used to search R-group from ZINC database. As a result, a series of R-groups with relatively high activity contribution was obtained. By No. 6 molecule filtering, 3 R_1 and 15 R_2 groups were selected, and employed to alternately substitute for the R_1 and R_2 of sample 6. Finally, 45 new compounds were designed, and the Topomer CoMFA model was used to predicate the biological activity, so the Topomer Search is effective in screening and can guide the design of new HIV/AIDS drugs. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 RT active site, which revealed the likely bioactive conformations. This study showed that there are extensive interactions between the 1,3,4-thiazolidinone revertase inhibitors and His84, Asp145, Lys33 and Leu83 residues in the active site of HIV-1 RT. These results provide useful insights for the design of potent new inhibitors of RT.展开更多
采用基于R基团搜索技术的Topomer Co MFA技术对一系列喹诺酮羧酸类衍生物进行三维定量构效(3D-QSAR)关系研究,所得模型结果的交叉验证相关系数(q2)为0.790,非交互验证系数(r2)为0.890,外部验证的复相关系数(r2pred)为0.878,研究结果表...采用基于R基团搜索技术的Topomer Co MFA技术对一系列喹诺酮羧酸类衍生物进行三维定量构效(3D-QSAR)关系研究,所得模型结果的交叉验证相关系数(q2)为0.790,非交互验证系数(r2)为0.890,外部验证的复相关系数(r2pred)为0.878,研究结果表明该模型具有良好的稳定性和预测能力。采用Topomer search技术在ZINC数据库中进行虚拟筛选,筛选出6个Ra基团和3个Rb基团,进而设计出12个具有更高活性的新型喹诺酮羧酸类化合物。采用分子对接技术对药物与受体的作用机制进行了研究,结果显示,药物与蛋白酶的ASP 30、ASP 29和ASN 25位点作用明显,该QSAR的研究结果可为新药合成提供理论参考。展开更多
The diarylpyrimidine(DAPY) compounds are important in the nonnucleoside reverse enzyme inhibitors. The present study is aimed at studying the three-dimensional quantitative structure-activity relationship(3D-QSAR) of ...The diarylpyrimidine(DAPY) compounds are important in the nonnucleoside reverse enzyme inhibitors. The present study is aimed at studying the three-dimensional quantitative structure-activity relationship(3D-QSAR) of DAPY inhibitors and their binding mode. We build a 3D-QSAR model involving 24 training DAPY inhibitors based on Topomer CoMFA, and 8 molecules are employed to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting, cross-validation and external validation were 0.979, 0.597 and 0.756, respectively. Topomer Search was employed as a tool for virtual screening in drug-like compounds of ZINC database(2012). Finally, we successfully design 30 new molecules with higher activity than that of all training and test inhibitors. The results indicated that Topomer CoMFA model had both favorable estimation stability and good predictive capability. Topomer Search technology could be effectively used to screen and design new compound, and had good predictive capability to guide the design of new Anti-HIV drugs. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 reverse transcriptase active site, which revealed the likely bioactive conformations. This study showed extensive interactions between the DAPY derivatives and MET230, TRP229, PHE227, TYR318, TYR183, PRO95, GLY99, ILE100,TYR188, VAL106, TYR181, GLY190, GLU138, VAL179, THR139, ASN103 and LYS101 residues in the active site of HIV-1 reverse transcriptase. These results provide useful insights for the design of potent new inhibitors of HIV-1 reverse transcriptase.展开更多
基金supported by the National Natural Science Foundation of China(21475081)Natural Science Foundation of Shaanxi Province(2015JM2057)Graduate Innovation Fund of Shaanxi University of Science and Technology
文摘Acquired Immunodeficiency Syndrome(AIDS) is a significant human health threat around the world. Therefore, the study of anti-human immunodeficiency virus(HIV) drug design has become an important task for today’s society. In this paper, a three-dimensional quantitative structure-activity relationships study(3 D-QSAR) was conducted on 53 HIV-1 integrase inhibitors(IN) using random sampling analysis on molecular surface(RASMS) and Topomer comparative molecular field analysis(Topomer CoMFA). The multiple correlation coefficients of fitting, cross-validation, and external validation of two models were 0.926, 0.815 and 0.908 and 0.930, 0.726 and 0.855, respectively. The results indicated that two models obtained had both favorable estimation stability and good prediction capability. Topomer Search was used to search appropriate R groups from ZINC database, and 28 new compounds were designed thereby. The Topomer CoMFA model was subsequently used to predict the biological activity of these compounds, showing that 24 of the new compounds were more active than the template molecule. Ligands of the template molecule and new designed compounds were used for molecular docking to study the interaction of these compounds with the protein receptor. The results show that the ligands would form hydrogen-bonding interactions with the residues LEU58, THR83, GLN62, MET155, LYS119 and ALA154 of the protein receptor generally, thereby providing additional insights for the design of even more effective HIV/AIDS drugs.
基金Supported by the National Natural Science Foundation of China(21475081)Natural Science Foundation of Shaanxi Province of China(2015JM2057)Graduate Innovation Fund of Shaanxi University of Science and Technology
文摘Peptides are one of the indispensable substances in life. The use of computer aided drug design(CADD) methods to design peptides and peptiodmimetics can short the design cycle, save research funding, improve the level of whole research to a large extent and guide the discovery of new drugs. In this paper, Melittin and amoebapore three-dimensional quantitative structureactivity relationship(3D-QSAR) models were established by using comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) method. The result shows that, the correlation coefficient(q^2) was 0.583 and non-cross-validation correlation coefficient(r^2) was 0.972 for the melittin CoMFA model. The q^2 and r^2 were 0.630 and 0.995 for the best CoMSIA model, 0.645 and 0.993 for the amoebapore CoMFA model, and 0.738 and 0.996 for the best CoMSIA model. The statistical parameters demonstrated that the CoMFA and CoMSIA models had both good predictive ability and high statistical stability, and can provide theoretical basis for designing new high activity polypeptide drugs.
文摘硫代氨基甲酸酯（TCS）被确认为一种新的非核苷类HIV-1逆转录酶抑制剂。本文采用基于R基团搜索技术的Topomer Co MFA方法。实验一对111个硫代氨基甲酸酯衍生物分子进行了三维定量构效关系分析,得到3D-QSAR模型的q^2为0.616,r^2为0.751,实验二对前60个分子进行同样的分析,得到q^2为0.777,r^2为0.913。两次实验结果表明所建立的模型在统计上都有较好的稳定性和预测能力,但相比之下,实验二更有利于抗艾滋病药物的设计。
基金supported by the National Natural Science Foundation of China(21475081,21275094)the Graduate Innovation Fund of Shaanxi University of Science and Technology
文摘In this paper, a three-dimensional quantitative structure-activity relationships(3 D-QSAR) study for 20 HIV-1 reverse transcriptase(RT) inhibitors was established using Topomer Co MFA. The models were built based on different fragment cutting models, with the most effective model of the multiple correlation coefficients of fitting(r^2) to be 0.920, cross-validation(q^2) of 0.575, and external validation(Q_(ext)~2) being 0.701. The results indicated that the model obtained has both favorable estimation stability and good prediction capability. Topomer Search was used to search R-group from ZINC database. As a result, a series of R-groups with relatively high activity contribution was obtained. By No. 6 molecule filtering, 3 R_1 and 15 R_2 groups were selected, and employed to alternately substitute for the R_1 and R_2 of sample 6. Finally, 45 new compounds were designed, and the Topomer CoMFA model was used to predicate the biological activity, so the Topomer Search is effective in screening and can guide the design of new HIV/AIDS drugs. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 RT active site, which revealed the likely bioactive conformations. This study showed that there are extensive interactions between the 1,3,4-thiazolidinone revertase inhibitors and His84, Asp145, Lys33 and Leu83 residues in the active site of HIV-1 RT. These results provide useful insights for the design of potent new inhibitors of RT.
基金supported by the National Natural Science Foundation of China(21475081,21275094)the Graduate Innovation Fund of Shaanxi University of Science and Technology
文摘The diarylpyrimidine(DAPY) compounds are important in the nonnucleoside reverse enzyme inhibitors. The present study is aimed at studying the three-dimensional quantitative structure-activity relationship(3D-QSAR) of DAPY inhibitors and their binding mode. We build a 3D-QSAR model involving 24 training DAPY inhibitors based on Topomer CoMFA, and 8 molecules are employed to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting, cross-validation and external validation were 0.979, 0.597 and 0.756, respectively. Topomer Search was employed as a tool for virtual screening in drug-like compounds of ZINC database(2012). Finally, we successfully design 30 new molecules with higher activity than that of all training and test inhibitors. The results indicated that Topomer CoMFA model had both favorable estimation stability and good predictive capability. Topomer Search technology could be effectively used to screen and design new compound, and had good predictive capability to guide the design of new Anti-HIV drugs. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 reverse transcriptase active site, which revealed the likely bioactive conformations. This study showed extensive interactions between the DAPY derivatives and MET230, TRP229, PHE227, TYR318, TYR183, PRO95, GLY99, ILE100,TYR188, VAL106, TYR181, GLY190, GLU138, VAL179, THR139, ASN103 and LYS101 residues in the active site of HIV-1 reverse transcriptase. These results provide useful insights for the design of potent new inhibitors of HIV-1 reverse transcriptase.
