文章基本信息

标题：Characterizing the pocketome of Mycobacterium tuberculosis and application in rationalizing polypharmacological target selection
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作者：Praveen Anand ; Nagasuma Chandra
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2014
卷号：4
DOI：10.1038/srep06356
出版社：Springer Nature
摘要：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.