非核苷类HIV-1逆转录酶抑制剂Ⅱ6-(1-萘甲基)胸腺嘧啶类化合物三维定量构效关系

目的 进一步研究6-(1-萘甲基)取代胸腺嘧啶类(HEPT)HIV-1逆转录酶抑制剂的构效关系。方法 利用比较分子力场分析方法(CoMFA)对14个新合成的6-(1-萘甲基)取代HEPT类似物进行三维定量构效关系研究；对化合物与HIV-1逆转录酶的非底物结合部分(NNBP)作用情况进行了对接(Dock)研究；并建立了回归方程。结果 用模型预测了2个6-(1-萘甲基)取代HEPT类化合物的-logEC50值，结果得以验证。空间立体效应占85．7％，静电立场效应占14．3％。结论 对接结果显示：在NNBP中，化合物以蝴蝶双翅形的构象伸展开来，并以芳环与结合腔表面的芳香性氨基酸残基产生疏水性相互作用。6-位引入(1-萘甲基)可显著提高化合物的生物活性，空间效应是影响活性的主要因素，此模型可为进一步的结构优化提供理论指导。     

2D, 3D-QSAR and docking studies of 1,2,3-thiadiazole thioacetanilides analogues as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

ABSTRACT: BACKGROUND: The discovery of clinically relevant inhibitors of HIV-RT for antiviral therapy has proven to be a challenging task. To identify novel and potent HIV-RT inhibitors the quantitative structure-activity relationship (QSAR) approach became very useful and largely widespread technique for ligand based drug design. METHODS: We perform the two- and three-dimensional (2D and 3D) QSAR studies of a series of 1,2,3-Thiadiazole thioacetanilides Analogues to elucidate the structural properties required for HIV-RT inhibitory activity. RESULTS: The 2D-QSAR studies were performed using multiple linear regression method (MLR), giving r2 = 0.97 and q2 = 0.94. The 3D-QSAR studies were performed using the stepwise variable selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2=0.89 and a non-cross-validated correlation coefficient r2=0.97 were obtained. Docking analysis suggests the new series have comparable binding affinity with the standard compounds. CONCLUSIONS: This approach showed that hydrophobic & electrostatic effects dominantly determine binding affinities which will further useful for development of new NNRTIs.     

Receptor and ligand-based 3D-QSAR study on a series of nonsteroidal anti-inflammatory drugs

Self-organizing molecular field analysis (SOMFA) has been used to study the correlation between the molecular properties of a series of 33 stilbene analogs and the cyclooxygenase-2 (COX-2) inhibitory activities. Thus, two different alignments and four charge-assigning methods using grid spacing of 1 Å were investigated to produce eight SOMFA models. The best one derived from the superposition of docked conformation with PM3 charge showed satisfied statistical results. It is characterized by a good noncross-validated r ² (0.806), cross-validated $ r_{\text{cv}}^{ 2} $ (0.799) and F test value (128.673). In addition, the resulted SOMFA model was validated by an external set of ten compounds. The statistical results, predicted correlation coefficient $ r_{\text{Test}}^{ 2} $  = 0.651, metric $ r_{{m({\text{Test}})}}^{ 2} $  = 0.514, and the squared correlation coefficient between observed and predicted values r ² = 0.762, show a satisfied predictive ability. The analysis of SOMFA model, through electrostatic and shape grids, helped in understanding the possible structural modifications of molecules to improve the inhibitory potency.     

Synergistic application of target structure-based alignment and 3D-QSAR study of protein tyrosine phosphatase 1B (PTP1B) inhibitors

Protein tyrosine phosphatase 1B (PTP1B) has been demonstrated to play a key role in the negative signaling pathway of insulin. Potent and orally active PTP1B inhibitors are considered to be promising pharmacological agents for the treatment of type 2 diabetes and resistance to weight gain. CoMFA studies were performed on a set of PTP1B inhibitors, which are known to bind simultaneously to the active site as well as a sub-binding site. An alignment, based on eight different crystal structure complexes of PTP1B was carried out to study the synergistic application of the alignment on CoMFA. The CoMFA model with statistical parameters r_\textcv ² = 0. 50 6,  r_\textncv ² = 0. 9 8 5 r_{\text{cv}}^{ 2} = 0. 50 6,\;r_{\text{ncv}}^{ 2} = 0. 9 8 5 , standard error of estimate 0.12, and F = 244.4 was found to be significant. The steric and electrostatic components presumably play an important role to achieve activity and selectivity in this series of molecules.     

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 2. Analogues of 3-aminopyridin-2(1H)-one.

A series of nonnucleoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties. Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC.dG as template-primer. Two compounds from this series, 3-[[(4,7-dimethylbenzoxazol-2-yl)methyl]-amino]-5-ethyl-6-methy lpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95% in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.