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

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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.

Original languageEnglish
Pages (from-to)1535-1557
Number of pages23
JournalDrug Design, Development and Therapy
Volume11
DOIs
StatePublished - 18 May 2017

Bibliographical note

Publisher Copyright:
© 2017 Meirson et al.

Funding

This work was supported by the Israel Science Foundation (grant number 996/12), the Israel Cancer Research Fund (grant number 12-709-RCDA), the Israel Cancer Association (grant number 20141043), the Marie Curie Career Integration Grant (grant number 321556), the Helmsley Charitable Trust Fund (grant number 2012PG-ISL013; to H.G.-H.), and the Leir Foundation and Katz Foundation (to A.O.S.).

FundersFunder number
Israel Cancer Research Fund12-709-RCDA
Leona M. and Harry B. Helmsley Charitable Trust2012PG-ISL013
Jerold B. Katz Foundation
Seventh Framework Programme321556
Leir Foundation
Marie Curie
Israel Cancer Association20141043
Israel Science Foundation996/12

    Keywords

    • Efficiency metrics
    • MM-GBSA
    • Molecular dynamics
    • Virtual screen

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