A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment.
A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment.
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DOI：
10.3390/ijms222413215
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发表时间：
2021-12-08
影响因子：
5.6
通讯作者：
Smieško M
中科院分区：
文献类型：
--
作者：
Fischer A;Smieško M
细胞色素P450酶（CYP）是参与人体药物代谢的最大酶群。配体通道将其埋在膜锚定蛋白核心的活性位点连接到周围的溶剂环境。最近，表面变构位点的证据，在这里表示为热点1（H1），参与调节的配体访问可溶性原核生物出现。在这里，我们应用多尺度计算建模技术来研究这个变构位点在9个最相关的哺乳动物CYP中的保守性和功能性，这些CYP负责大约70%的药物代谢。总的来说，我们系统地分析了超过44秒的轨迹，从传统的MD，共溶剂MD，和metadhesics模拟。我们的生物信息学分析和模拟与有机探针分子揭示了该网站是很好的保守的CYP2家族的CYP2E1除外。在存在与H1位点结合的配体的情况下，我们可以观察到CYP 2家族的几个成员中配体通道的扩大。此外，尽管除CYP2C19、CYP2E1和CYP3A4外的所有其他酶均呈现类似趋势，但我们可以检测到H1相互作用对CYP2C8和CYP2D6中配体易位的促进作用具有统计学显著性。由于配体进入和流出现象的详细理解仍然是该领域最相关的挑战之一，这项工作有助于其阐明，并最终有助于使用计算技术估计代谢转化的选择性。
Cytochrome P450 enzymes (CYPs) are the largest group of enzymes involved in human drug metabolism. Ligand tunnels connect their active site buried at the core of the membrane-anchored protein to the surrounding solvent environment. Recently, evidence of a superficial allosteric site, here denoted as hotspot 1 (H1), involved in the regulation of ligand access in a soluble prokaryotic CYP emerged. Here, we applied multi-scale computational modeling techniques to study the conservation and functionality of this allosteric site in the nine most relevant mammalian CYPs responsible for approximately 70% of drug metabolism. In total, we systematically analyzed over 44 s of trajectories from conventional MD, cosolvent MD, and metadynamics simulations. Our bioinformatic analysis and simulations with organic probe molecules revealed the site to be well conserved in the CYP2 family with the exception of CYP2E1. In the presence of a ligand bound to the H1 site, we could observe an enlargement of a ligand tunnel in several members of the CYP2 family. Further, we could detect the facilitation of ligand translocation by H1 interactions with statistical significance in CYP2C8 and CYP2D6, even though all other enzymes except for CYP2C19, CYP2E1, and CYP3A4 presented a similar trend. As the detailed comprehension of ligand access and egress phenomena remains one of the most relevant challenges in the field, this work contributes to its elucidation and ultimately helps in estimating the selectivity of metabolic transformations using computational techniques.
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DOI：
10.1073/pnas.062565599
发表时间：
2002-05-14
影响因子：
11.1
作者：
Bayburt, TH;Sligar, SG
通讯作者：
Sligar, SG
影响因子：
5.5
作者：
Borrelli, KW;Vitalis, A;Guallar, V
通讯作者：
Guallar, V
影响因子：
4.6
作者：
Fischer, Andre;Smiesko, Martin
通讯作者：
Smiesko, Martin
影响因子：
6.8
作者：
Furst, Maximilian J. L. J.;Fiorentini, Filippo;Fraaije, Marco W.
通讯作者：
Fraaije, Marco W.
影响因子：
5.8
作者：
Kozlikova, Barbora;Sebestova, Eva;Sochor, Jiri
通讯作者：
Sochor, Jiri