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An in silico high-throughput screen identifies potential selective inhibitors for the non-receptor tyrosine kinase Pyk2

Authors Meirson T, Samson AO, Gil-Henn H

Received 10 March 2017

Accepted for publication 28 March 2017

Published 18 May 2017 Volume 2017:11 Pages 1535—1557

DOI https://doi.org/10.2147/DDDT.S136150

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Rajendra Narayan Mitra

Peer reviewer comments 2

Editor who approved publication: Dr Sukesh Voruganti

Tomer Meirson, Abraham O Samson, Hava Gil-Henn

Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel

Abstract: The non-receptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) is a critical mediator of signaling from cell surface growth factor and adhesion receptors to cell migration, proliferation, and survival. Emerging evidence indicates that signaling by Pyk2 regulates hematopoietic cell response, bone density, neuronal degeneration, angiogenesis, and cancer. These physiological and pathological roles of Pyk2 warrant it as a valuable therapeutic target for invasive cancers, osteoporosis, Alzheimer’s disease, and inflammatory cellular response. Despite its potential as a therapeutic target, no potent and selective inhibitor of Pyk2 is available at present. As a first step toward discovering specific potential inhibitors of Pyk2, we used an in silico high-throughput screening approach. A virtual library of six million lead-like compounds was docked against four different high-resolution Pyk2 kinase domain crystal structures and further selected for predicted potency and ligand efficiency. Ligand selectivity for Pyk2 over focal adhesion kinase (FAK) was evaluated by comparative docking of ligands and measurement of binding free energy so as to obtain 40 potential candidates. Finally, the structural flexibility of a subset of the docking complexes was evaluated by molecular dynamics simulation, followed by intermolecular interaction analysis. These compounds may be considered as promising leads for further development of highly selective Pyk2 inhibitors.

Keywords: virtual screen, efficiency metrics, MM-GBSA, molecular dynamics

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