Costache A D, Trawick D, Bohl D, Sem D S
Chemical Proteomics Facility at Marquette, Department of Chemistry, P.O. Box 1881, Marquette University, Milwaukee, Wisconsin 53201, USA.
Xenobiotica. 2007 Mar;37(3):221-45. doi: 10.1080/00498250601089162.
Organic amines are prevalent in nature and in drugs, especially the psychotherapeutic agents, and a major defense against potentially toxic amines is metabolism by CYP2D6. In order to understand better the constraints on the broad specificity of CYP2D6, 4207 amines were docked into the binding site of this enzyme. Docking poses were found predominantly with the positively charged amino groups closest to Asp301, with aromatic rings close to Phe120 and sometimes extending as far as Phe483. Organic amines that bind best to CYP2D6 tend to have larger molecular weights and logP values. Organic amines that score highly as being druglike, based on a Bayesian model constructed using a 5223-drug training set, are least likely to bind to CYP2D6. This correlation suggests that the set of known drugs, which have been largely designed or selected to avoid high affinity CYP binding, partially encodes the binding site preferences (or rather anti-preferences) of CYP2D6. Finally, in order to benchmark our docking and druglike scoring procedures, an analysis of psychotherapeutic agents is presented. All of these data, including the 4207 AM1-optimized ligand structures in proper ionization states, docking poses and scores, Druglike Scores and Lipinski properties, can be viewed from an online database, the AmineDB.
有机胺在自然界和药物中普遍存在，尤其是在精神治疗药物中，而针对潜在有毒胺的主要防御机制是通过细胞色素P450 2D6（CYP2D6）进行代谢。为了更好地理解对CYP2D6广泛特异性的限制，将4207种胺对接至该酶的结合位点。对接姿势主要表现为带正电荷的氨基最靠近天冬氨酸301（Asp301），芳香环靠近苯丙氨酸120（Phe120），有时可延伸至苯丙氨酸483（Phe483）。与CYP2D6结合最佳的有机胺往往具有更大的分子量和脂水分配系数（logP）值。基于使用5223种药物训练集构建的贝叶斯模型，得分高的类药物有机胺与CYP2D6结合的可能性最小。这种相关性表明，已知药物组在很大程度上是为避免与CYP具有高亲和力而设计或选择的，其部分编码了CYP2D6的结合位点偏好（或者更确切地说是反偏好）。最后，为了对我们的对接和类药物评分程序进行基准测试，对精神治疗药物进行了分析。所有这些数据，包括处于适当电离状态的4207种AM1优化配体结构、对接姿势和分数、类药物分数和Lipinski性质，均可从在线数据库AmineDB中查看。
