Characterizing the pocketome of Mycobacterium tuberculosis and application in rationalizing polypharmacological target selection

Anand, Praveen and Chandra, Nagasuma (2014) Characterizing the pocketome of Mycobacterium tuberculosis and application in rationalizing polypharmacological target selection. In: SCIENTIFIC REPORTS, 4 .

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Abstract

Polypharmacology is beginning to emerge as an important concept in the field of drug discovery. However, there are no established approaches to either select appropriate target sets or design polypharmacological drugs. Here, we propose a structural-proteomics approach that utilizes the structural information of the binding sites at a genome-scale obtained through in-house algorithms to characterize the pocketome, yielding a list of ligands that can participate in various biochemical events in the mycobacterial cell. The pocket-type space is seen to be much larger than the sequence or fold-space, suggesting that variations at the site-level contribute significantly to functional repertoire of the organism. All-pair comparisons of binding sites within Mycobacterium tuberculosis (Mtb), pocket-similarity network construction and clustering result in identification of binding-site sets, each containing a group of similar binding sites, theoretically having a potential to interact with a common set of compounds. A polypharmacology index is formulated to rank targets by incorporating a measure of druggability and similarity to other pockets within the proteome. This study presents a rational approach to identify targets with polypharmacological potential along with possible drugs for repurposing, while simultaneously, obtaining clues on lead compounds for use in new drug-discovery pipelines.

Item Type:	Journal Article
Publication:	SCIENTIFIC REPORTS
Publisher:	NATURE PUBLISHING GROUP
Additional Information:	Copyright for this article belongs to the NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND.
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	08 Nov 2014 05:07
Last Modified:	08 Nov 2014 05:07
URI:	http://eprints.iisc.ac.in/id/eprint/50163

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