Homology model, molecular dynamics simulation and novel pyrazole analogs design of Candida albicans CYP450 lanosterol 14 α-demethylase, a target enzyme for antifungal therapy. Issue 7 (19th May 2017)

• Record Type: Journal Article
• Authors: Jacob K., Sony; Ganguly, Swastika; Kumar, Pravin; Poddar, Raju; Kumar, Anoop
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 35:Issue 7(2017)
• Page Start: 1446
• Page End: 1463
• Publication Date: 2017-05-19
• Subjects: Candida albicans -- homologous model -- pyrazole analogs -- docking study -- toxicity study; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2016.1185380
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract : Candida albicans infections and their resistance to clinically approved azole drugs are major concerns for human. The azole antifungal drugs inhibit the ergosterol synthesis by targeting lanosterol 14α-demethylase of cytochrome P450 family. The lack of high-resolution structural information of fungal pathogens has been a barrier for the design of modified azole drugs. Thus, a preliminary theoretical molecular dynamic study is carried out to develop and validate a simple homologous model using crystallographic structure of the lanosterol 14α-demethylase of Mycobacterium tuberculosis (PDB ID-1EA1) in which the active site residues are substituted with that of C. albicans (taxid 5476). Further, novel designed pyrazole analogs (SGS1-16 ) docked on chimeric 1EA1 and revealed that SGS-16 show good binding affinity through non-bonding interaction with the heme, which is different from the leading azole antifungals. The ADME-T results showed these analogs can be further explored in design of more safe and effective antifungal agents.