title: Structure-based de novo design, synthesis, and biological evaluation of non-azole inhibitors specific for lanosterol 14alpha-demethylase of fungi.
abstract: The active site of lanosterol 14alpha-demethylase (CYP51) was investigated via MCSS functional group mapping and LUDI calculations. Several non-azole lead molecules were obtained by coupling structure-based de novo design with chemical synthesis and biological evaluation. All of the lead molecules exhibited a strong inhibitory effect on CYP51 of Candida albicans. They occupy the substrate-binding site and interfere with the binding of azole antifungal agents in a competitive manner. The mode of action of the lead molecules was validated by spectrophotomeric analysis and SAR studies. This is the first successful example reported for the inhibitor design of the cytochrome P450 superfamily using the de novo design strategy. Because the affinity of the lead molecules for CYP51 was mainly attributed to their nonbonding interaction with the apoprotein, the studies presented here afford the opportunity to develop novel antifungal agents that specifically interact with the residues in the active site and avoid the serious toxicity arising from coordination binding with the heme of mammalian P450s.
authors.affiliation: School of Pharmacy and Department of Microbiology, Second Military Medical University, Shanghai 200433, China. jihaitao@chem.nwu.edu
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Makiko
authors.initials: M
authors.lastname: Kudo
authors.forename: Yuri
authors.initials: Y
authors.lastname: Aoyama
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Song
authors.forename: Song
authors.initials: S
authors.lastname: Yang
authors.forename: Youjun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jiaguo
authors.initials: J
authors.lastname: Lü
authors.forename: Jü
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D002176:Candida albicans / Q000737:chemistry; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005658:Fungi / Q000737:chemistry*; D006418:Heme / Q000737:chemistry; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013053:Spectrophotometry; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D001578:Benzopyrans; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006418:Heme; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase