Structure-based de novo design, synthesis, and biological evaluation of non-azole inhibitors specific for lanosterol 14alpha-demethylase of fungi.
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.
Ji
Haitao
H
School of Pharmacy and Department of Microbiology, Second Military Medical University, Shanghai 200433, China. jihaitao@chem.nwu.edu
Zhang
Wannian
W
Zhang
Min
M
Kudo
Makiko
M
Aoyama
Yuri
Y
Yoshida
Yuzo
Y
Sheng
Chunquan
C
Song
Yunlong
Y
Yang
Song
S
Zhou
Youjun
Y
Lü
Jiaguo
J
Zhu
Jü
J
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
D000935:Antifungal Agents; D001578:Benzopyrans; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006418:Heme; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase