Prediction of Sites of Metabolism of CYP3A4 Substrates Utilizing Docking-Derived Geometric Features,Journal of Chemical Information and Modeling

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Prediction of Sites of Metabolism of CYP3A4 Substrates Utilizing Docking-Derived Geometric Features
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2023-06-19 , DOI: 10.1021/acs.jcim.3c00549
Yanjun Feng ₁ , Changda Gong ₁ , Jieyu Zhu ₁ , Guixia Liu ₁ , Yun Tang ₁ , Weihua Li ₁

Affiliation

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.

中文翻译：

利用对接衍生的几何特征预测 CYP3A4 底物的代谢位点

细胞色素 P450 3A4 (CYP3A4) 是人体内主要的药物代谢酶之一，负责约 50% 的临床使用药物的代谢。因此，在药物发现和开发的早期阶段，鉴定由 CYP3A4 介导的化合物代谢位点 (SOM) 至关重要。在此，结合几何特征的基于对接的方法被用于 CYP3A4 底物的 SOM 预测。对包含 474 个基质的相对较大数据集的越库姿势进行了深入分析，并从这些姿势中得出了广泛观察到的称为 SOM 紧密接近的几何图案。在紧密接近的基础上，构建了几种基于结构的模型，与使用 Fe-SOM 距离标准的基于结构的模型相比，它表现出更好的性能。为了进一步提高预测性能，基于结构的模型还与著名的基于配体的模型 SMARTCyp 相结合。一种组合模型在包含激酶抑制剂、PROTAC、已批准药物和一些先导化合物的外部底物组的 SOM 预测上表现出良好的性能。

更新日期：2023-06-19

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