Abstract 4496: A computational initiative to determine the role of dietary polyphenols against oncogenic KRAS mutants
Authors: Chatterjee Prarthana , Karn Rohit , Chakraborty Sohini , Sinha Saptarshi , Ghosh Pradipta , Banerjee Satarupa 
Published: March 2024

Abstract
Introduction: Two oncogenic driver mutants (G12C and G14D) of KRAS have been reported to drive tumorigenesis in several cancers and targeting the switch I/II domain of mutant KRAS oncoprotein can be an efficient strategy for inhibiting the mutated KRAS-driven tumors. Modern clinical therapeutics are often associated with several adverse side effects and the eventual development of multi-drug resistance. Herein, exhaustive computational strategies are employed in designing dietary polyphenol-based small molecule inhibitors against such oncogenic KRAS tumors.
Methodology: Integrated bioinformatics strategies such as pharmacokinetic property prediction, analysis of medicinal chemistry profile, density functional theory (DFT) study, molecular docking, molecular dynamics simulation (MDS) and principal component analysis were performed to screen 930 dietary polyphenols to identify potent inhibitors against the G12C and G14D mutants. Sotorasib, an FDA-approved KRAS chemotherapeutic inhibitor was used as a reference drug in this study.
Results: Out of the 930 dietary polyphenols screened, based on the properties of pharmacokinetic descriptors and medicinal chemistry profile, 512 molecules were shortlisted for further studies. Five dietary polyphenols viz. Quercetin, Luteolin, Peonidin 3-O-glucoside, Myricetin, and Kaempferol identified via DFT and MDS exhibited the highest binding affinity and optimum energy profiles with our selected mutants G12C and G14D. An all-atom MDS study executed over 200 ns each revealed that Quercetin, Luteolin, and Peonidin 3-O-glucoside show favorable thermodynamic stability with significantly less conformational perturbations with G12C mutant. By contrast, mutant G12D complexed with Kaempferol and Myricetin exhibited the least thermodynamic flexibility and stable backbone trajectory, when compared to clinically standardized KRAS inhibitor Sotorasib. The efficient and higher binding stability of the polyphenols targeting the KRAS mutants, G12C and G14D switches I/II is mainly attributed to the formation of hydrogen bonds and other hydrophobic interactions at the molecular level. All five evaluated polyphenols qualified the parameters of cell-line cytotoxicity hinting at remarkable chemotherapeutic efficacy.
Conclusion: Computer-aided drug designing performed here aided the identification of natural dietary polyphenolic inhibitors as potential drug candidates exhibiting stable binding dynamics like Sotorasib, which thus awaits validation through further in-vitro analyses in inhibiting KRAS-driven tumorigenesis.
Citation Format: Prarthana Chatterjee, Rohit Karn, Sohini Chakraborty, Saptarshi Sinha, Pradipta Ghosh, Satarupa Banerjee. A computational initiative to determine the role of dietary polyphenols against oncogenic KRAS mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4496.