Structural insights into the inhibitor binding and new inhibitor design to Polo-like kinase-1 Polo-box domain using computational studies.

J Biomol Struct Dyn 2019 Aug 1;37(13):3410-3421. Epub 2018 Nov 1.

a School of Chemistry , University of Hyderabad , Hyderabad , India.

Polo box domain (PBD) from Polo-Like Kinase-1 (PLK-1) a cell cycle regulator is one of the important non-kinase targets implicated in various cancers. The crystal structure of PLK-1 PBD bound to phosphopeptide inhibitor is available and acylthiourea derivatives have been reported as potent PBD inhibitors. In this work, structure and ligand-based pharmacophore methods have been used to identify new PBD inhibitors. The binding of acylthiourea analogs and new inhibitors to PBD were assessed using molecular docking and molecular dynamics simulations to understand their binding interactions, investigate the complex stability and reveal the molecular basis for inhibition. This study provides the binding free energies and residue-wise contributions to decipher the essential interactions in the protein-inhibitor complementarity for complex formation and the design of new PBD inhibitors with better binding. Communicated by Ramaswamy H. Sarma.

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Source
https://www.tandfonline.com/doi/full/10.1080/07391102.2018.1
Publisher Site
http://dx.doi.org/10.1080/07391102.2018.1515663DOI Listing
August 2019
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