In silico identification of potential drug targets in Clostridium difficile R20291 : modeling and virtual screening anal
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Med Chem Res (2013) 22:2692–2705 DOI 10.1007/s00044-012-0262-0
ORIGINAL RESEARCH
In silico identification of potential drug targets in Clostridium difficile R20291: modeling and virtual screening analysis of a candidate enzyme MurG Vijayalakshmi Ezhilarasan • Om Prakash Sharma Archana Pan
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Received: 12 March 2012 / Accepted: 27 September 2012 / Published online: 10 October 2012 Ó Springer Science+Business Media New York 2012
Abstract Clostridium difficile is an etiologic agent of a variety of gastrointestinal diseases in human including mild sporadic diarrhea and severe life-threatening pseudomembranous colitis. The continuous rise of C. difficile infection worldwide accompanied by rapid emergence of multidrugresistant and hypervirulent strains has necessitated the search for novel drug targets. The present study is aimed at identifying putative therapeutic targets in this pathogen by in silico approach which encompassed four steps, viz, similarity search between pathogen and host, essentiality study using the database of essential genes, metabolic functional association study using Kyoto Encyclopedia of Genes and Genomes database, and choke point analysis. The study identified 19 promising drug targets which are non-homologous to host proteins, potentially essential for the pathogen, choke point enzymes, and participate in four pathogenspecific pathways, namely peptidoglycan biosynthesis, phosphotransferase system, two component system, and D-alanine metabolism pathways. The peptidoglycan biosynthesis pathway is the highest donor to the list of candidate target proteins. Furthermore, a three-dimensional model of one of the identified potential targets, MurG from peptidoglycan biosynthesis pathway, was constructed by homology Electronic supplementary material The online version of this article (doi:10.1007/s00044-012-0262-0) contains supplementary material, which is available to authorized users. V. Ezhilarasan O. P. Sharma A. Pan (&) Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet 605014, Pondicherry, India e-mail: [email protected]; [email protected] V. Ezhilarasan e-mail: [email protected] O. P. Sharma e-mail: [email protected]
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modeling. Subsequently, by means of a virtual screening approach, the study identified eight potential inhibitors from small molecules databases, which have better docking scores, varying from -7.9 to -10.3 kcal/mol, and stronger binding affinity with target compared to known inhibitors and natural substrate of MurG. The docking analysis revealed that the active site residue Gln298 plays a critical role in ligand–target interactions which was validated through in silico mutational study. Other active site residues like Arg168, Ser198, Arg202, Ser269, and His297 were also found to play a role in binding interactions. The identified compounds may facilitate the development of new drugs to combat C. difficile-associated diseases. Keywords Clostridium difficile Drug target MurG Modeling Docking study Inhibitor
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