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PLoS Comput Biol. 2017 Jun 29;13(6):e1005522. doi: 10.1371/journal.pcbi.1005522. eCollection 2017 Jun.

Detecting similar binding pockets to enable systems polypharmacology.

Author information

1
Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain.
2
Molecular Discovery Limited, London, United Kingdom.
3
Department of Computer Science & Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America.
4
School of Computer Sciences, Tel Aviv University, Tel Aviv, Israel.
5
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
6
Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Catalonia, Spain.
7
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
8
Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.

Abstract

In the era of systems biology, multi-target pharmacological strategies hold promise for tackling disease-related networks. In this regard, drug promiscuity may be leveraged to interfere with multiple receptors: the so-called polypharmacology of drugs can be anticipated by analyzing the similarity of binding sites across the proteome. Here, we perform a pairwise comparison of 90,000 putative binding pockets detected in 3,700 proteins, and find that 23,000 pairs of proteins have at least one similar cavity that could, in principle, accommodate similar ligands. By inspecting these pairs, we demonstrate how the detection of similar binding sites expands the space of opportunities for the rational design of drug polypharmacology. Finally, we illustrate how to leverage these opportunities in protein-protein interaction networks related to several therapeutic classes and tumor types, and in a genome-scale metabolic model of leukemia.

PMID:
28662117
PMCID:
PMC5490940
DOI:
10.1371/journal.pcbi.1005522
[Indexed for MEDLINE]
Free PMC Article

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