Rupp Bernd, Raub Stephan, Marian Christel, Höltje Hans-Dieter
Institute of Pharmaceutical Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225, Düsseldorf, Germany.
J Comput Aided Mol Des. 2005 Mar;19(3):149-63. doi: 10.1007/s10822-005-3692-7.
Sterol 14alpha-demethylase (CYP51) is one of the known major targets for azole antifungals. Therapeutic side effects of these antifungals are based on interactions of the azoles with the human analogue enzyme. This study describes for the first time a comparison of a human CYP51 (HU-CYP51) homology model with a homology model of the fungal CYP51 of Candida albicans (CA-CYP51). Both models are constructed by using the crystal structure of Mycobacterium tuberculosis MT-CYP51 (PDB code: 1EA1). The binding mode of the azole ketoconazole is investigated in molecular dynamics simulations with the GROMACS force field. The usage of special parameters for the iron azole complex binding is necessary to obtain the correct complex geometry in the active site of the enzyme models. Based on the dynamics simulations it is possible to explain the enantioselectivity of the human enzyme and also to predict the binding mode of the isomers of ketoconazole in the active site of the fungal model.
甾醇14α-去甲基酶（CYP51）是已知的唑类抗真菌药物的主要靶点之一。这些抗真菌药物的治疗副作用基于唑类与人类同源酶的相互作用。本研究首次描述了人类CYP51（HU-CYP51）同源模型与白色念珠菌真菌CYP51（CA-CYP51）同源模型的比较。这两个模型均通过使用结核分枝杆菌MT-CYP51的晶体结构（PDB代码：1EA1）构建。使用GROMACS力场在分子动力学模拟中研究了唑类酮康唑的结合模式。为了在酶模型的活性位点获得正确的复合物几何结构，需要使用铁唑复合物结合的特殊参数。基于动力学模拟，有可能解释人类酶的对映选择性，并预测酮康唑异构体在真菌模型活性位点的结合模式。
