苯基氨基吡啶派生物类非核苷类HIV-1逆转录酶抑制剂HQSAR研究及分子设计

HQSAR study and molecular design of Phenylaminopyridine(PAP) derivatives as HIV-1 nonnucleoside reverse transcriptase inhibitors

采用分子全息定量构效关系(HQSAR)方法,研究了21个HIV-1逆转录酶抑制剂苯基氨基吡啶派生物(Phenylaminopyridine,PAP)类化合物的构效关系;探讨了碎片区分参数、分子碎片大小和分子全息长度对模型质量的影响;建立了一组以16个化合物为训练集的最优模型,其交叉验证相关系数q^2为0.801,非交叉验证相关系数r^2为0.963,标准偏差为0.363;对5个化合物构成的测试集进行了预测,其相关系数r_(pred)~2为0.92,表明该模型具有良好的预测能力。最后,通过HQSAR模型色码图对PAP类化合物的活性起重要作用的片段与结构进行了讨论,并根据HQASR最佳模型图设计出了20种PAP派生物类化合物,这些化合物理论上均具有较好的抗HIV-1活性,为PAP派生物类化合物的进一步合成提供理论指导。

A hologramquantitative structure-activity relationship（HQSAR） studies were conducted on a series of 21 Phenylamin opyridine（PAP） derivatives as HIV-1 reverse transcriptase inhibitors. The influences of fragment distinction, fragment size and hologram length on the quality of the models were investigated. The best HQSAR model was obtained for the 16 training set compounds showing cross-validated q2value of 0.801, conventional r2 value of 0.963 and standand deviation SEE was 0.363. The model was then externally validated using a test set of 5 compounds and the predicted values were in good agreement with the experimental results （r2pr-0.92）. The color code analysis based on the obtained HQSAR model provided useful insights into the chemical and structural features of PAP derivatives for their HIV-1 inhibitory potency.Based on the best model HQSAR, 27 new PAP derivatives were designed and screened using the optimal HQSAR model, giving potential candidates with high predictive anti-HIV-1 activity. This work provides valuable information for further design and synthesis more promising PAP derivatives as NNRTIs.