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

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

Volume: 18 Issue: 8

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

Affiliation:

• Laboratoire des Materiaux Polymères Multiphasiques, LMPMP, Universite Ferhat ABBAS Setif-1, 19000 Setif,Algeria

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

Abstract:

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.

Cite this article as:

Attoui Ayoub , Sobhi Widad , Hammoudi El Houda Nour and Benguerba Yacine *, Fragment-based Drug Design of Antitumoral Molecules Polo-like Kinase 1 Inhibitors: In-silico Approach, Letters in Drug Design & Discovery 2021; 18 (8) . https://dx.doi.org/10.2174/1570180818999201230195526