Computational study for the identification of phytochemical from Acacia hydaspica as potent inhibitor for addressing KRAS-related non-small cell lung cancer: Perspectives on ligand-based drug discovery

• KRAS mutations are the most common oncogenic drivers in advanced non-small cell lung cancer (NSCLC), occurring in approximately 30% of lung adenocarcinomas. • The study addresses the lack of in-silico research on the inhibition of KRAS mutations by small molecules. • Phytochemicals from Acacia hydaspica were investigated as potential inhibitors of KRAS mutations. • CG's lowest PC3 value in PCA and DCCM analysis, indicating its effectiveness as a KRAS inhibitor. • Promising potential anti-cancer drug for NSCLC through computational drug discovery methods. The KRAS (Kirsten rat sarcoma virus oncogene homolog) gene, the most ordinary oncogenic driver in advanced NSCLC (non-small cell lung cancer), is mutated in around 30% of lung adenocarcinomas. Since there hasn't been any in-silico research on the inhibition of KRAS mutation by small molecules. Consequently, this research aimed to identify phytochemicals in Acacia hydaspica that could serve as therapeutic mediators to inhibit the progress of NSCLC cells with the mutant KRAS. Therefore, a protein with a distinct inhibitor and a particular binding pocket containing amino acid residues for the suppression of GTPase activity was chosen (PDB ID: 8FMI ). Four hits were reported from a structure-based virtual screening using molecular-docking calculations. C7OG, Cianidanol, CG and MG had docking scores of -9.2 kcal.mol −1 , -8.8 kcal.mol −1 , -8.7 kcal.mol −1 , and -6.5 kcal.mol −1 , respectively. After docking, we rejected MG for lower docking score. CG were deemed lead molecule because it performed better in docking assessments, ADMET, PASS prediction, and drug-likeness prediction analysis than the Adagrasib (control) KRAS inhibitor. The compound “CG” showed better stability when in complex with the target protein during the MD simulation time compare to C7OG, Cianidanol and Control compounds. In PCA and DCCM analysis, Compound should be lowest PC3 value rather than the others compounds which indicating that it would be a good inhibitor of KRAS activity. So, CG creates more stable complex with the apoprotein. In this study, CG as a KRAS inhibitor identified as a potential anti-cancer medicine for NSCLC using computational drug discovery technologies.