Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
J Chem Inf Model. 2023 Jul 10;63(13):4158-4169. doi: 10.1021/acs.jcim.3c00549. Epub 2023 Jun 19.
Cytochrome P450 3A4 (CYP3A4) is one of the major drug-metabolizing enzymes in the human body and is responsible for the metabolism of ∼50% of clinically used drugs. Therefore, the identification of the compound's sites of metabolism (SOMs) mediated by CYP3A4 is of utmost importance in the early stage of drug discovery and development. Herein, docking-based approaches incorporating geometric features were used for SOMs prediction of CYP3A4 substrates. The cross-docking poses of a relatively large data set containing 474 substrates were analyzed in depth, and a widely observed geometric pattern called the close proximity of SOMs was derived from the poses. On the basis of the close proximity, several structure-based models have been constructed, which demonstrated better performance than those structure-based models using the criterion of Fe-SOM distance. For further improving the prediction performance, the structure-based models were also combined with the well-known ligand-based model SMARTCyp. One combined model exhibited good performance on the SOMs prediction of an external substrate set containing kinase inhibitors, PROTACs, approved drugs, and some lead compounds.
细胞色素 P450 3A4（CYP3A4）是人体内主要的药物代谢酶之一，负责代谢约 50%的临床应用药物。因此，在药物发现和开发的早期阶段，鉴定由 CYP3A4 介导的化合物代谢部位（SOMs）至关重要。本文采用基于对接的方法结合几何特征，对 CYP3A4 底物的 SOMs 进行预测。对包含 474 个底物的相对较大数据集的交叉对接构象进行了深入分析，并从这些构象中得出了一种广泛观察到的几何模式，称为 SOMs 的近距离。基于这种近距离，构建了几个基于结构的模型，这些模型在使用 Fe-SOM 距离标准的基于结构的模型的性能更好。为了进一步提高预测性能，还将基于结构的模型与著名的基于配体的模型 SMARTCyp 相结合。一个组合模型在激酶抑制剂、PROTACs、已批准药物和一些先导化合物的外部底物集的 SOMs 预测中表现出良好的性能。
