Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
Volume 116, Issue -, Pages 173-181Publisher
ELSEVIER
DOI: 10.1016/j.ijbiomac.2018.05.023
Keywords
PLK-1; Ser/Thr kinases; Cancer therapy; Cell cycle arrest; Schrodinger; Docking and simulation
Funding
- Deanship of Scientific Research at King Saud University, Riyadh, Kingdom of Saudi Arabia [RGP-150]
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Polo-like kinase-1 (PLK-1) plays a key role in cell cycle progression during mitosis. Overexpression/dysfunction of PLK-1 is directly associated with cancerous transformation and has been reported in different cancer types. Here, we employed high throughput virtual screening and molecular docking to screen Selleck's natural compound library against PLK-1 kinase domain. We have identified eight bioactive compounds (Apigenin, Dihydromyricetin, Diosmetin, Hesperidin, Hesperitin, Naringenin, Phlorizi, and Quercetin) as the potential inhibitors of PLK-1. Further investigation through Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations and 15 ns molecular dynamics simulation revealed that hesperidin formed the most stable complex with PLK-1 kinase domain. Altogether, our results indicate that hesperidin interacted strongly with the key residues of the PLK-1 active site (such as Leu59, Lys61, Lys82, Cys133, Asnl 81, Asp194, Leu59, Cys67, Ala80, Va1114, Leu130, Leu132, Cys133, Leul 39, Phe183, and Phe195) through hydrogen bonding and hydrophobic interactions. The Hesperidin-PLK-1 complex was stabilized by Gibb's free energy of-13.235 kcal/mol which corresponded to the binding affinity of 5.095 x 10(9) M-1. This is the first study wherein hesperidin has been identified as a potential inhibitor of PLK-1. Further design and optimization of the hesperidin scaffold as an inhibitor of PLK-1 kinase domain is highly recommended. (C) 2018 Elsevier B.V. All rights reserved.
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