Computational Exploration of Potential Polo-Like Kinase 1 Inhibitors as New Chemotherapeutic Agents
Mubarak A. Alamri *
Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O.Box 173, Al-Kharj 11942, Saudi Arabia.
Ahmed D. Alafnan
Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail, Saudi Arabia.
*Author to whom correspondence should be addressed.
Abstract
Background and Objective: Polo like kinase-1 (PLK-1) enzyme belongs to serine/threonine protein kinase family that is regarded as a principle mitotic controller of G2-M phase transition. The antimitotic therapies are a cornerstone for the treatment of metastatic as well as benign cancer. Therefore, PLK-1 has recently gained much interest in the field of targeting it by novel and effective inhibitors.
Materials and Methods: The present study described the used of pharmacophore modelling based on the potent and selective clinical agent, Volasertib and followed by hybrid selection of a kinase inhibitors databank of 4800 diverse compounds by pharmacophore- and docking-based virtual screening.
Results: The retrieved hits were filtered on the bases of their pharmacophore-fit scores, docking binding affinity scores, ADME-T profiles as well as ligand quality assessments. Among the five hit compounds that fulfil the criterion, three compounds, Z1991791422, Z56115729 and Z1991791176 were selected for binding dynamic analyses by molecular dynamic simulation. The Z1991791422 and Z56115729 compounds illustrated stable binding behaviours at the proposed binding site. Conclusion: Thus, these compounds might emerge as potent inhibitors of PLK1 and could be applied as seeds for designing better PLK1 inhibitors in near future.
Keywords: Autodock Vina, ligandscout, polo like kinase-1, pharmacophore, virtual screening, molecular simulation.