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.
