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.
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.
采用三维全息原子场作用矢量(3D-HoVAIF)对20个TIBO类衍生物抗艾滋病药物进行定量构效关系(QSAR)研究。运用偏最小二乘回归(Partial Least Square Regression,PLS)建模,同时采用内部及外部双重验证的办法对所得模型稳定性能进行深入分析和检验。PLS建模的复相关系数(Rcum)、留一法(Leave-one-out,LOO)交互校验(Cross-validation,CV)复相关系数(QCV)和外部样本校验复相关系数(Qext)分别为0.837、0.804、0.812。结果表明,3D-HoVAIF能较好表征TIBO类衍生物抗艾滋病药物分子结构信息,
采用分子表面随机采样分析对26个香豆素类衍生物抗艾滋病药物进行定量构效关系研究。运用多元线性回归(multiple linear regression,MLR)建模,同时采用内部及外部双重验证的办法对所得模型稳定性能进行深入分析和检验。MLR建模的复相关系数(_(cum)~2)、留一法(1eave-one-out,LOO)交互校验(cross-validation,CV)复相关系数(Q_(CV)~2)和外部样本校验复相关系数r^2(test)分别为0.936、0.894、0.772。结果表明,RASMS能较好表征香豆素类衍生物抗艾滋病药物分子的结构信息,且所建模型具有良好稳定性和预测能力,可用于研发新型HIV整合酶抑制剂。
