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

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.

Proline-Rich Protein Tyrosine Kinase 2 in Inflammation and Cancer

“…Increasing evidence has demonstrated that FAK/Pyk2 signaling regulates hematopoietic cell differentiation, bone mass formation, neuronal degeneration, inflammatory response and cancer. Therefore, Pyk2 is a valuable therapeutic target for inflammatory diseases and malignancies [ 80 , 81 ]. Based on protein structure, targeting tyrosine kinases has focused on the ATP binding pocket to inhibit catalytic activity and repress the pathways involved in carcinogenesis, EMT and metastasis.…”

Decoys Selection in Benchmarking Datasets: Overview and Perspectives

“…In SBVS, tuned datasets should be used to identify the protocol, conformational sampling, and/or scoring methods that induces the best enrichment in active compounds (Allen et al, 2015 , 2017 ; Lacroix et al, 2016 ; Li et al, 2016 ; Nunes et al, 2016 ; Meirson et al, 2017 ). For instance, Allen et al ( 2015 , 2017 ) evaluated different scoring schemes using DUD-E generated decoys and successfully identified dual EFGR/BRD4 inhibitors.…”

“…An automated tool was made available online to generate decoys from user-supplied ligands using the same protocol ( http://decoys.docking.org ). The possibility to generate decoy sets for any target has been revealed successful and is now widely used by the scientific community (Lacroix et al, 2016 ; Nunes et al, 2016 ; Allen et al, 2017 ; Meirson et al, 2017 ).…”

Significance of PYK2 level as a prognosis predictor in patients with colon adenocarcinoma after surgical resection

“…The potential of PYK2 in tumor therapy is attracting more attentions due to recent development of PYK2 inhibitors. 38 , 39 Several PYK2 inhibitors had been reported to exert tumor-suppressing role in bone tumors and breast cancer. 40 – 42 For example, the PF-562,271 is a potent, ATP-competitive, reversible inhibitor of PYK2.…”