Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
J Chem Inf Model. 2015 Mar 23;55(3):660-6. doi: 10.1021/ci500653b. Epub 2015 Feb 20.
Many drug compounds are oxidized by cytochrome P450 (CYP) enzymes to form reactive metabolites. This study presents density functional theory calculations of the CYP-mediated metabolism of acetaminophen and a series of related compounds that can form reactive metabolites by hydrogen abstraction. The substitution pattern affects the activation barrier for hydrogen abstraction by up to 30 kJ/mol. A correlation (R(2) = 0.72) between the transition-state energies and the corresponding substrate radical energies has been established. Using this correlation is significantly less time-demanding than using the porphyrin model to determine the activation energies. We have used this correlation on monosubstituted phenols to rationalize the effect of the various substituents in the drug compounds. In addition to facilitating a chemical interpretation, the approach is sufficiently fast and reliable to be used as an in silico method in the design of new compounds with improved metabolic stability.
许多药物化合物被细胞色素 P450（CYP）酶氧化形成反应性代谢物。本研究通过密度泛函理论计算了对乙酰氨基酚和一系列相关化合物的 CYP 介导的代谢，这些化合物可以通过氢提取形成反应性代谢物。取代模式对氢提取的活化能的影响高达 30 kJ/mol。已经建立了过渡态能量与相应的底物自由基能量之间的相关性（R(2) = 0.72）。与使用卟啉模型来确定活化能相比，使用这种相关性的时间要求明显减少。我们已经在单取代苯酚上使用了这种相关性，以合理说明药物化合物中各种取代基的影响。除了促进化学解释外，该方法足够快速和可靠，可以用作新化合物设计中提高代谢稳定性的计算方法。
