Identification of novel pyrazole containing ɑ-glucosidase inhibitors: insight into pharmacophore, 3D-QSAR, virtual screening, and molecular dynamics study

Pharmacophore modelling, 3 D QSAR modelling, virtual screening, and molecular dynamics study, all-in-one combination were employed successfully design and develop an alpha-glucosidase inhibitor. To explain the structural prerequisites of biologically active components, 3 D-QSAR models were generated using the selected best hypothesis (AARRR) for compounds 55 included in the model C. The selection of 3 D-QSAR models showed that the Gaussian steric characteristic is crucial to alpha glucosidase’s inhibitory potential. The alpha-glucosidase inhibitory potency of the compound is enhanced by other components, including Gaussian hydrophobic groups, Gaussian hydrogen bond acceptor or donor groups, Gaussian electrostatic characteristics, and a Gaussian steric feature. An identification of structure-activity relationships can be obtained from the developed 3 D-QSAR, C model, with R² = 0.77 and SD = 0.02 for training set, and Q² = 0.66, RMSE 0.02, and Pearson R = 0.81 for testing set, corresponding to elevated predictive ability. Additionally, docking and MM/GBSA experiments on 1146023 showed that it interacts with critical amino acids in the binding site when coupled with acarbose. Further, five compounds that display a high affinity for alpha-glucosidase were found, and these compounds may serve as potent leads for alpha-glucosidase inhibitor development. Biological activity will be tested for these compounds in the future. Communicated by Ramaswamy H. Sarma

本研究整合药效团建模（Pharmacophore modelling）、三维定量构效关系（3D QSAR）建模、虚拟筛选与分子动力学模拟技术，成功设计并开发了α-葡萄糖苷酶抑制剂。为阐明生物活性成分的结构先决条件，本研究针对模型C中收录的55个化合物，采用筛选得到的最优假设（AARRR）构建了三维定量构效关系（3D-QSAR）模型。三维定量构效关系模型的筛选结果表明，高斯空间特征对α-葡萄糖苷酶的抑制活性至关重要。其余特征参数，包括高斯疏水基团、高斯氢键供体/受体基团、高斯静电特征以及另一高斯空间特征，均可提升化合物的α-葡萄糖苷酶抑制活性。基于构建的3D-QSAR C模型，可明确其构效关系：训练集的R²=0.77、标准差（SD）=0.02；测试集的Q²=0.66、均方根误差（RMSE）=0.02、皮尔逊相关系数（Pearson R）=0.81，表明该模型具备优异的预测能力。此外，针对化合物1146023开展的分子对接（docking）与分子力学/广义玻恩表面积（MM/GBSA）实验结果显示，该化合物与阿卡波糖共同作用时，可与酶结合位点内的关键氨基酸产生相互作用。研究进一步筛选得到5个对α-葡萄糖苷酶具有高亲和力的化合物，此类化合物可作为开发α-葡萄糖苷酶抑制剂的强效先导化合物。后续将对上述化合物开展生物活性测试。本文由Ramaswamy H. Sarma转交刊发。