Insights into the Selective Inhibition of Candida albicans Secreted Aspartyl Protease: A Docking Analysis Study

• Published in: Bioorganic & medicinal chemistry Vol. 10; no. 4; pp. 1153 - 1170
• Main Authors: Pranav Kumar, S.K., Kulkarni, Vithal M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2002; Elsevier Science
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Biological and medical sciences; Candida albicans - drug effects; Candida albicans - enzymology; Catalytic Domain; Computer Simulation; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Inhibitory Concentration 50; Ligands; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Piperazines - chemistry; Piperazines - pharmacology; Thermodynamics; Candida albicans; Molecular rigidity; Sulfanilamide derivatives; Cyclohexane derivatives; Enzyme; Nitrogen heterocycle; Peptidomimetic compound; Active site; Lactam; Non peptide compound; Inhibitor enzyme complex; Modeling; Fungi; Peptidases; Antifungal agent; Three dimensional model; Structure activity relation; Molecular model; Hydrolases; Carboxamide; Ureas; Aspartic endopeptidases; Fungi Imperfecti; Thallophyta
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(01)00385-6

Severe fungal infections have taken precedence over other bacterial infections. Of the several fungal species, Candida albicans and others belonging to the genus Candida are responsible for several clinically important fungal infections. Emerging cases of drug resistance to the currently available drugs has limited the spectrum of currently available antifungal agents. Thus, it is imperative that new biochemical targets are identified so that better effective and selective agents can be developed. Many enzymes contribute towards the complex disease process of fungal infections; the secreted aspartyl protease (SAP), expressed both in vitro and during infection, has been implicated as one of the major virulence factors of C. albicans. Three-dimensional crystal structures of C. albicans SAP and closely related clinical isolate designated as SAP2X complexed with the same potent inhibitor A-70450 have been reported. Several analogues of A-70450 with potent C. albicans SAP2X inhibitory activity are also known. However, the structural effects of the binding of these compounds with the enzyme active site are not completely understood. Our efforts in this direction involve the docking analysis of C. albicans SAP2X inhibitors complexed with SAP2X enzyme, which is reported in this work. Docking analysis was performed on a set of molecules with differing selectivities and inhibitory potencies towards C. albicans, renin and cathepsin D. The structural effects of ligand binding were analyzed on the basis of hydrophobic and hydrogen bond interactions, binding energy analysis, interaction energies, rms deviations, etc. in the resulting energy-minimized structures of the receptor–ligand complexes. Structural analysis of the resulting models indicates that hydrophobic and hydrogen bonding interactions together with binding and interaction energies are responsible for selective inhibition of C. albicans SAP2X. Hydrophobic and hydrogen bonding interactions in the various subsites of the enzyme, contributing to both increase as well as decrease in selectivity of the molecules have been detailed. Hydrogen bonding interaction plays an important role for amino acid residues such as Gly-85, Asp-86, Asp-32, Asp-218, Tyr-225, Ala-133, and so on. Significant hydrophobic interactions with the S3, S2 and S2′ subsites contribute to selectivity of the compounds. These molecular modeling analyses should, in our view, contribute for further development of selective C. albicans secreted aspartyl protease inhibitors. Docking analysis performed on Candida albicans secreted aspartyl protease complexed with selective inhibitors (analogues of compound A-70450) has revealed the importance of hydrophobic and hydrogen bond interactions in mediating the inhibitor selectivity and potency. This analysis should be useful in the design of selective non-peptidic inhibitors of C. albicans aspartyl protease.