Exploring 2D-QSAR for prediction of beta-secretase 1 (BACE1) inhibitory activity against Alzheimer’s disease

We have developed a robust quantitative structure–activity relationship (QSAR) model employing a dataset of 98 heterocycle compounds to identify structural features responsible for BACE1 (beta-secretase 1) enzyme inhibition. We have used only 2D descriptors for model development purpose thus avoiding the conformational complications arising due to 3D geometry considerations. Following the strict Organization for Economic Co-operation and Development (OECD) guidelines, we have developed models using stepwise regression analysis followed by the best subset selection, while the final model was developed by partial least squares regression technique. The model was validated using various internationally accepted stringent validation parameters. From the insights obtained from the developed model, we have concluded that heteroatoms (nitrogen, oxygen, etc.) present within to an aromatic nucleus and the structural features such as hydrophobic, ring aromatic and hydrogen bond acceptor/donor are responsible for the enhancement of the BACE1 enzyme inhibitory activity. Moreover, we have performed the pharmacophore modelling to unveil the structural requirements for the inhibitory activity against the BACE1 enzyme. Furthermore, molecular docking studies were carried out to understand the molecular interactions involved in binding, and the results are then correlated with the requisite structural features obtained from the QSAR and pharmacophore models.本研究构建了一款稳健的定量构效关系（quantitative structure–activity relationship, QSAR）模型，采用包含98种杂环化合物的数据集，旨在识别与β-分泌酶1（BACE1，beta-secretase 1）酶抑制活性相关的结构特征。本研究仅使用二维描述符开展模型构建，从而规避了因三维几何结构考量所引发的构象复杂性问题。本研究严格遵循经济合作与发展组织（Organization for Economic Co-operation and Development, OECD）指南，先通过逐步回归分析结合最优子集选择构建模型，最终采用偏最小二乘回归技术得到最优模型。该模型通过多项国际公认的严苛验证参数完成了有效性验证。基于所构建模型得到的分析结果，本研究得出结论：芳香环内核中的杂原子（氮、氧等）以及疏水结构、芳香环结构、氢键供体/受体等结构特征，可增强BACE1酶的抑制活性。此外，本研究开展了药效团建模，以揭示BACE1酶抑制活性所需的结构条件。进一步通过分子对接实验解析了配体与靶点的结合分子相互作用机制，并将该结果与从QSAR模型及药效团模型中得到的关键结构特征进行了关联分析。