School of Pharmacy, Kitasato University, Tokyo, Japan.
Drug Metab Pharmacokinet. 2013;28(4):345-55. doi: 10.2133/dmpk.dmpk-12-rg-133. Epub 2013 Jan 29.
Cytochrome P450 3A4 (CYP3A4) is a member of the CYP family and is an important enzyme in drug metabolism. A compound that inhibits CYP3A4 activity could also affect the pharmacokinetics of other substrates, resulting in drug-drug interactions (DDIs) that could cause side effects. Pharmacokinetic data from drug-development studies in rats often determine the dosage used in human clinical trials. It is therefore useful to understand differences in metabolism in different species at an early stage in drug development. Human and rat CYP3A enzymes show different inhibition profiles with different drugs, although the mechanisms involved are not yet clear. Here we built three-dimensional quantitative structure-activity relationship (3D-QSAR) models using structure-based comparative molecular field analysis (CoMFA), to predict the direct inhibitory activity of ligands for human CYP3A4 and rat CYP3A1, based on computer-ligand docking. The alignment of the ligand docking poses suggested that key amino acid-ligand interactions (e.g., Thr309 in CYP3A4 and Pro310 in CYP3A1) characterized the different potencies with which the ligands inhibited CYP3A4 and CYP3A1. The 3D-QSAR models for human and rat CYP3A family inhibitors predicted the potency of inhibitors and could be useful for assessing DDIs at an early stage in drug discovery.
细胞色素 P450 3A4（CYP3A4）是 CYP 家族的一员，是药物代谢中的重要酶。抑制 CYP3A4 活性的化合物也可能影响其他底物的药代动力学，导致药物相互作用（DDI），从而引起副作用。来自大鼠药物开发研究的药代动力学数据通常决定了在人类临床试验中使用的剂量。因此，在药物开发的早期阶段，了解不同物种的代谢差异是很有用的。尽管涉及的机制尚不清楚，但人和大鼠 CYP3A 酶对不同的药物表现出不同的抑制谱。在这里，我们使用基于结构的比较分子场分析（CoMFA）构建了三维定量构效关系（3D-QSAR）模型，基于计算机配体对接，预测配体对人 CYP3A4 和大鼠 CYP3A1 的直接抑制活性。配体对接构象的比对表明，关键的氨基酸-配体相互作用（例如，CYP3A4 中的 Thr309 和 CYP3A1 中的 Pro310）表征了配体抑制 CYP3A4 和 CYP3A1 的不同效力。人 CYP3A 家族抑制剂的 3D-QSAR 模型预测了抑制剂的效力，可用于在药物发现的早期阶段评估药物相互作用。
