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首页> 外文期刊>Journal of chemical information and modeling >Structure-Based Rational Screening of Novel Hit Compounds with Structural Diversity for Cytochrome P450 Sterol 14α-Demethylase from Penicillium digitatum
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Structure-Based Rational Screening of Novel Hit Compounds with Structural Diversity for Cytochrome P450 Sterol 14α-Demethylase from Penicillium digitatum

机译：基于结构合理筛选具有数字多样性的青霉菌细胞色素P450甾醇14α-脱甲基酶命中化合物

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摘要

Cytochrome P450 sterol 14α-demethylases (CYP51s) are essential enzymes in sterol biosynthesis and wellknown as the target of antifungal drugs. All fungal CYP51s are integral membrane proteins, making structural and biophysical characterization more challenging. The X-ray crystallographic structure of CYP51 isolated from Mycobacterium tuberculosis (MT-CYP51) is the unique reported one hitherto. In the present study, a homology modeling three-dimensional structure of CYP51 from Penicillium digitatum (PD-CYP51) was generated by CPHmodels, in which the accuracy of sequence alignment could be improved by taking into account further structural conservation information, using MT-CYP51 as the template. Interaction mechanism between the active site of PD-CYP51 and its inhibitors were further investigated by molecular dynamics simulating and molecular docking. With the effective docking process and interaction analysis information, structure-based virtual screening was performed to pick out the thirty new potential inhibiting compounds with structural diversity by using a new virtual screening strategy including Flex-Pharm/PMF/GOLD//FlexX/ PMF/GOLD molecular docking procedures, and finally, seven new hit compounds out of SPECs database with potent inhibitory ability were validated by bioaffinity assays at enzyme level and on P. digitatum in vitro. The positive results indicated that all modeling strategies and screening processes presented in the current study most like to be an encouraging way in search of novel lead compounds with structural diversity for the specifically individual fungal CYP51s of both plants and human pathogens in the future.
机译：细胞色素P450固醇14α-脱甲基酶（CYP51s）是固醇生物合成中必不可少的酶，众所周知是抗真菌药物的靶标。所有真菌CYP51s是必不可少的膜蛋白，使结构和生物物理表征更具挑战性。从结核分枝杆菌（MT-CYP51）分离出的CYP51的X射线晶体学结构是迄今为止唯一的报道。在本研究中，通过CPHmodels生成了由指状青霉（CYP51）CYP51三维结构的同源性建模三维模型，其中使用MT-CYP51考虑到更多的结构保守性信息可以提高序列比对的准确性。作为模板。通过分子动力学模拟和分子对接研究了PD-CYP51活性位点与其抑制剂之间的相互作用机理。借助有效的对接过程和相互作用分析信息，使用包括Flex-Pharm / PMF / GOLD // FlexX / PMF /在内的新虚拟筛选策略，进行了基于结构的虚拟筛选，以挑选出三十种具有结构多样性的潜在抑制化合物。 GOLD分子对接程序，最后，通过酶亲和力法和体外对数位假单胞菌的生物亲和力试验，验证了SPECs数据​​库中具有有效抑制能力的七个新命中化合物。积极的结果表明，当前研究中提出的所有建模策略和筛选过程都最有可能成为寻找具有结构多样性的新型先导化合物以用于未来植物和人类病原体的特定真菌CYP51s的令人鼓舞的方法。

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