Low molecular weight ligands bind to CYP3A4 via a branched induced fit mechanism: Implications for O2 binding.
Low molecular weight ligands bind to CYP3A4 via a branched induced fit mechanism: Implications for O2 binding.
复制标题
低分子量配体通过分支诱导拟合机制与 CYP3A4 结合：对 O2 结合的影响。
DOI：
10.1016/j.abb.2023.109582
复制
发表时间：
2023
影响因子：
3.9
通讯作者：
Atkins,WilliamM
中科院分区：
文献类型：
--
作者：
Redhair,Michelle;Nath,Abhinav;Hackett,JohnC;Atkins,WilliamM
肝细胞色素P450（CYP）是一个非常重要的O2依赖性血红素单加氧酶家族，它代谢或被大多数小分子药物抑制，导致不可预测的药物相互作用。CYP 3A 4是代谢依赖性药物相互作用的主要贡献者。CYP 3A 4的一个标志是其底物混杂性，这通常归因于“构象灵活性”。在无底物状态下，如果不同的构象招募不同的底物，快速平衡的构象系综可以促进混杂[1，2];构象系综扩大了相互作用的底物范围。基于动力学标准[2，3]，这种“构象选择”（CS）已被建议用于肝CYP结合MW>~ 400 Da的原型药物或抑制剂[4]，如无配体构象系综所预期的。值得注意的是，相同作者先前将无CS的诱导拟合（IF）归因于CYP 3A 4-配体相互作用，强调需要进行更严格的分析[4]。IF和CS都可能有助于药物与CYP的结合，并且动力学特征可能是配体依赖性的，原因我们之前已经描述过[2]。CS行为的一个被忽视的方面是这样一个事实，即无配体状态下的构象系综对结合共底物O2是有害的，除非它以类似的高速率结合所有构象。如果没有，那么构象集合与许多药物相互作用的功能优势可能会被具有O2结合不太迅速或紧密的某些构象的缺点所抵消。直觉上，如果小分子如O2在它们的构象偏好上固有地较少区分，则该缺点将自然地被克服。假设，小分子将以相似的速率接近无配体构象系综的成员，从而掩盖CS的任何动力学指纹，与较大药物分子的建议相反[1，4]，从而避免任何构象强加的缺点。
Hepatic Cytochrome P450s (CYPs) are a pharmacologically important family of O2-dependent heme-containing monooxygenases, which metabolize or are inhibited by most small-molecule drugs, resulting in unpredictable drug interactions. CYP3A4 is the dominant contributor to metabolism-dependent drug interactions. A hallmark of CYP3A4 is its substrate promiscuity, which is frequently ascribed to ‘conformational flexibility.’In the substrate-free state, rapidly equilibrating conformational ensembles can contribute to promiscuity if different conformations recruit different substrates [1, 2]; the conformational ensemble expands the range of substrates that interact. Based on kinetic criteria [2, 3], such ‘conformational selection’(CS) has been suggested for hepatic CYPs binding prototypical drugs or inhibitors with MW>~ 400 Da [4] as expected for a ligand-free conformational ensemble. Notably, induced fit (IF) without CS was previously ascribed to CYP3A4-ligand interactions by the same authors, emphasizing the need for more rigorous analyses [4]. Both IF and CS are likely to contribute for drugs binding to CYPs and the kinetic signature may be ligand-dependent for reasons we described previously [2]. An overlooked aspect of the CS behavior is the fact that conformational ensembles in the ligand-free state would be detrimental to binding the co-substrate, O2, unless it binds to all conformers with similarly high rates. If not, then the functional advantage of the conformational ensemble for interacting with many drugs could be offset by the disadvantage of having some conformations for which O2 bound less rapidly or tightly. Intuitively, this disadvantage would naturally be overcome if small molecules such as O2 are inherently less discriminating in their conformational preference. Hypothetically, small molecules would access members of the ligand free conformational ensemble with similar rates, thus masking any kinetic fingerprint of CS, in contrast to the suggestion for larger drug molecules [1, 4], and thus avoid any conformationallyimposed disadvantage.