title: Homology model, molecular dynamics simulation and novel pyrazole analogs design of Candida albicans CYP450 lanosterol 14 α-demethylase, a target enzyme for antifungal therapy.
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.
authors.affiliation: a Department of Pharmaceutical Sciences and Technology , Birla Institute of Technology, Mesra , Ranchi , Jharkhand 835215 , India.
authors.forename: Sony
authors.initials: S
authors.lastname: Jacob K
authors.affiliation: a Department of Pharmaceutical Sciences and Technology , Birla Institute of Technology, Mesra , Ranchi , Jharkhand 835215 , India.
authors.forename: Swastika
authors.initials: S
authors.lastname: Ganguly
authors.affiliation: b Department of Bio-Engineering , Birla Institute of Technology, Mesra , Ranchi , Jharkhand 835215 , India.
authors.forename: Pravin
authors.initials: P
authors.lastname: Kumar
authors.affiliation: b Department of Bio-Engineering , Birla Institute of Technology, Mesra , Ranchi , Jharkhand 835215 , India.
authors.forename: Raju
authors.initials: R
authors.lastname: Poddar
authors.affiliation: a Department of Pharmaceutical Sciences and Technology , Birla Institute of Technology, Mesra , Ranchi , Jharkhand 835215 , India.
authors.forename: Anoop
authors.initials: A
authors.lastname: Kumar
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002176:Candida albicans / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000201:enzymology / Q000235:genetics; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D058886:Sterol 14-Demethylase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D001426:Bacterial Proteins; D005656:Fungal Proteins; D011720:Pyrazoles; D011993:Recombinant Fusion Proteins; D058886:Sterol 14-Demethylase
keywords: Candida albicans; docking study; homologous model; pyrazole analogs; toxicity study