Improved Model of Lanosterol 14α‐Demethylase by Ligand‐Supported Homology Modeling: Validation by Virtual Screening and Azole Optimization |
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| Authors: | Chunquan Sheng Dr. Wenya Wang Dr. Xiaoying Che Dr. Guoqiang Dong Shengzheng Wang Haitao Ji Dr. Zhenyuan Miao Dr. Jianzhong Yao Dr. Wannian Zhang Prof. |
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| Affiliation: | 1. School of Pharmacy, Military Key Laboratory of Medicinal Chemistry, Second Military Medical University, 325 Guohe Road, Shanghai 200433 (People's Republic of China), Fax: (+86)?21‐81871243;2. Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology and Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL 60208‐3113 (USA) |
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| Abstract: | Lanosterol 14α‐demethylase (CYP51) is an important target for antifungal drugs. An improved three‐dimensional model of CYP51 from Candida albicans (CACYP51) was constructed by ligand‐supported homology modeling and molecular dynamics simulations. The accuracy of the constructed model was evaluated by its performance in a small‐scale virtual screen. The results show that known CYP51 inhibitors were efficiently discriminated by the model, and it performed better than our previous CACYP51 model. The active site of CACYP51 was characterized by multiple copy simultaneous search (MCSS) calculations. On the basis of the MCSS results, a series of novel azoles were designed and synthesized, and they showed good in vitro antifungal activity with a broad spectrum. The MIC80 value of four of these compounds against C. albicans is 0.001 μg mL?1, indicating that they are promising leads for the discovery of novel antifungal agents. |
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| Keywords: | active sites antifungal agents azoles cytochromes homology modeling |
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