KRAS is the most common altered oncogene of the RAS family in human tumors emerging as an attractive target for various human tumors. KRAS is found to be responsible for activating mutations upto 90% in pancreatic cancers and 50% in colorectal cancers. The present study involved retrieving a set of compounds from the ZINC database based on the best pharmacophore hypothesis/model and the optimal 3D-QSAR model (R 2 = 0.943; Q 2 = 0.9423), indicating strong correlation and predictive ability, along with low standard deviation (SD = 0.3987) and RMSE (0.38). In addition, 3D contour maps were examined to identify favorable and unfavorable regions for enhancing drug activity. The selected compounds were further screened through virtual molecular docking studies using PDB ID: 7O83. Three compounds-ZINC1911582104, ZINC1911585886, and ZINC1569989248 demonstrated comparable XP docking scores of -9.281, -8.112, and -7.261, respectively, relative to the standard drug Sotorasib (docking score: -9.232).Also, ADME studies suggested drug-like characteristics of the compounds ZINC1911582104, ZINC1911585886 and ZINC1569989248. Further, molecular dynamics simulation studies supported the stability of the ligand-protein complex during the course of the simulation. As a result, the present research may help scientists in beating the fight against undruggable KRAS target.
Wahan et al. (Fri,) studied this question.