Mukherjee Goutam, Lal Gupta Pancham, Jayaram B
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi-110016, India.
Mol Biosyst. 2015 Jul;11(7):1914-24. doi: 10.1039/c5mb00118h.
Metabolism studies are an essential integral part of ADMET profiling of drug candidates to evaluate their safety and efficacy. Cytochrome P-450 (CYP) metabolizes a wide variety of xenobiotics/drugs. The binding modes of these compounds with CYP and their intrinsic reactivities decide the metabolic products. We report here a novel computational protocol, which comprises docking of ligands to heme-containing CYPs and prediction of binding energies through a newly developed scoring function, followed by analyses of the docked structures and molecular orbitals of the ligand molecules, for predicting the sites of metabolism (SOM) of ligands. The calculated binding free energies of 121 heme-containing protein-ligand docked complexes yielded a correlation coefficient of 0.84 against experiment. Molecular orbital analyses of the resultant top three unique poses of the docked complexes provided a success rate of 87% in identifying the experimentally known sites of metabolism of the xenobiotics. The SOM prediction methodology is freely accessible at .
代谢研究是候选药物ADMET分析中不可或缺的一部分，用于评估其安全性和有效性。细胞色素P-450（CYP）可代谢多种外源性物质/药物。这些化合物与CYP的结合模式及其固有反应性决定了代谢产物。我们在此报告一种新颖的计算方法，该方法包括将配体与含血红素的CYP进行对接，并通过新开发的评分函数预测结合能，然后分析对接结构和配体分子的分子轨道，以预测配体的代谢位点（SOM）。121个含血红素的蛋白质-配体对接复合物的计算结合自由能与实验结果的相关系数为0.84。对接复合物所得前三个独特构象的分子轨道分析在识别外源性物质的实验已知代谢位点方面的成功率为87%。SOM预测方法可在[具体网址]免费获取。
