Abdeen Tunde Ogunlana

Conference 2024 Live Talk

Talk Title

Computer-aided drug design of some KRAS G12C inhibitors: Targeting the covalent and allosteric binding site for cancer therapy

Authors and Affiliations

Abdeen Tunde Ogunlana 1,5, Abdul-Quddus Kehinde Oyedele 1,6, Ibrahim Damilare Boyenle 1,5, Sukurat Oluwatoyin Ayoola 2, Abosede Christiana Ajibare 3, Ayodeji Oluwadamilare Adeyemi 4,Lukmon Akanni Jinadu 5, Oluwafemi Timothy Adenrele 6, Abdullahi Opeyemi Alausa 7,Temitope Isaac Adelusi 1.

1 Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria
2 Department of Public Health, Adeleke University, Ede, Osun State, Nigeria
3 Department of Biochemistry, University of Lagos, Lagos, Nigeria
4 Department of Medical Laboratory Technology, Lagos State College of Health Technology, Lagos, Nigeria
5 Department of Chemical Sciences, Biochemistry Unit, College of Natural and Applied Science, Fountain University, Nigeria
6 Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria
7 Department of Biochemistry and Nutrition, Nigerian Institute of Medical Research (NIMR), Yaba, Lagos, Nigeria.

Abstract

Background

KRAS is one of the most investigated anticancer targets today, owing to its common mutations in a variety of lethal malignancies. KRAS G12C has been the focus of cancer research since the identification of the druggable allosteric binding site located in close vicinity with G12C mutation.

Methods

A computer-aided drug discovery strategy was employed to identify new and selective KRAS G12C covalent inhibitors. An online database containing millions of assayed and curated compounds targeting KRAS G12C was screened, resulting in the generation of 1001 compounds. Subsequently, a ligand-filtering process was applied to isolate compounds with an acrylamide warhead group capable of covalently binding to the Cys12 nucleophile of KRAS G12C, akin to the clinically approved drug sotorasib. The 202 identified compounds underwent a covalent-docking virtual screening experiment to pinpoint three potential binders (CID_13728717, CID_146235508, and CID_146235420) against KRAS G12C in its inactive GDP-bound conformation.

Results

in silico ADMETox modeling and molecular dynamics investigations were then conducted to assess the drug-like properties and stability of the covalent binders. The molecular enumeration profile of CID_13728717 stood out as the most satisfactory, surpassing the standard drug, sotorasib in this computationally driven drug discovery research.

Conclusions

Based on these findings, CID_13728717 is likely to emerge as an effective KRAS G12C drug candidate, pending extensive experimental validation. The study underscores the potential of computer-aided drug design in identifying promising candidates for further exploration in anticancer therapeutics targeting KRAS G12C.