Abstract：
Combined in silico strategy for molecular mechanisms exploration of a series 3H-thiazolo[4,5-b]pyridin-2-ones exhibiting strong anti-exudative action through QSAR analysis, molecular docking and pharmacophore modelling is reported. GA-ML technique was used for QSAR models generation with 2D autocorrelation descriptors. One- and two-parameter regressions revealed that certain structural patterns or heteroatoms contribute mutually to the anti-exudative activity potentiation. Possible action mechanisms were discovered through flexible docking simulations with cyclooxygenase pathway enzymes (COX-1, COX-2, mPGES-1). Docking results indicated the possibility of stable complexes formation with the effective docking scores and proper orientation of ligands within the enzymes active sites. Pharmacophore modelling was carried out using protein-ligand interaction fingerprints methodology. Two- and three-centre 3D pharmacophore queries were constructed. Their analysis indicated the functionality of bicyclic thiazolopyridine scaffold proved by the steric placement of heteroatoms in the corresponding pharmacophore centres.
摘要：
通过QSAR分析，探索一系列3H-噻唑并[4,5-b]吡啶-2-酮的分子机制，据报道，分子对接和药效基团建模。GA-ML技术用于具有2D自相关描述符的QSAR模型生成。一参数和两参数回归表明，某些结构模式或杂原子相互有助于抗渗出活性增强。通过与环氧合酶途径酶（COX-1，COX-2，mPGES-1）的灵活对接模拟发现了可能的作用机制。对接结果表明，在酶活性位点内具有有效对接得分和配体适当取向的稳定复合物形成的可能性。使用蛋白质-配体相互作用指纹图谱方法进行药效团建模。构建了二中心和三中心3D药效团查询。他们的分析表明，双环噻唑并吡啶支架的功能通过相应药效团中心中杂原子的空间位置得到证明。
