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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Fragment-based Drug Design of Antitumoral Molecules Polo-like Kinase 1 Inhibitors: In-silico Approach

Author(s): Ayoub Attoui, Widad Sobhi, Nour El Houda Hammoudi and Yacine Benguerba*

Volume 18 , Issue 8 , 2021

Published on: 30 December, 2020

Page: [779 - 794] Pages: 16

DOI: 10.2174/1570180818999201230195526

Price: $65


Background: Kinase enzymes are reported to be very implicated in cancer. Polo-like kinase 1 (PLK1) is a protein kinase with a marked role in tumorigenesis and its inhibition is a promising anticancer therapeutic development strategy.

Objective: The purpose of this study was de novo design of new PLK1 inhibitors using in-silico approach.

Methods: A virtual compound library based on known inhibitors was designed using BREED algorithm. Molecules were geometrically optimized then filtered according to lead-like properties using QiqProp. Receptor-ligand complex-based pharmacophore model was generated with Phase and used to virtually screen the new virtual database. Glide multistage molecular docking simulations were performed for the resulted compounds followed with a Prime MM-GBSA minimization.

Results: Two compounds (prd-comp 1-2) showed acceptable binding poses with a higher docking score than known inhibitor BI2536. MM-GBSA study confirmed that the leads have better binding energy than reference ligands. All leads bind to the key amino acids Cys133, Leu59, with a focus on molecule prd-comp1, proposed to have better affinity due to direct H-bond with Asp194.

Conclusion: Modifying hydration pattern of target protein by displacing water molecule is suggested to be a promising strategy for designing new PLK1 inhibitors. This applied methodology and the retrieved hits could be useful in the design of potent inhibitors of PLK1 as antitumoral agents.

Keywords: Pharmacophore, virtual screening, docking, PLK1, inhibitor, antitumoral.

Graphical Abstract

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