Identification of Novel Potent KRASG12D Inhibitors Through Target-Based Virtual Screening

Cancer, a complex and multifaceted group of diseases, is a leading cause of death worldwide. Cancer leads to uncontrolled cell growth and has the capacity to spread to nearby tissues. There are different approaches reported for cancer treatment. Notably, 25% of cancer cases are because of mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog) protein that lead to cancer cell proliferation and angiogenesis. Recently, the Food and Drug Administration (FDA) has granted approval for Adagrasib and Sotorasib for use in adult patients in metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) [Lanman, B. A. et al., J. Med. Chem. 63, 52 (2020), Li, Y., Han, L., Zhang, Z., Comput. Struct. Biotechnol. J. 20, 1056 (2022)]. Here, we have used the AutoDock Vina tool to perform a docking-based virtual screening of the 7,00,000 commercially available compounds in the ZINC database against the KRASG12D (PDB ID: 6GJ5). The top-ranked 50 compounds, identified from the ZINC database, were analyzed for binding modes, binding affinities, and drug-likeness properties. We found three hit compounds whose binding affinities were comparable to the reported reference compound 15 (a known KRASG12D inhibitor). In conclusion, using an in silico approach, we have identified novel hit compounds that need further in vitro analysis to confirm their KRASG12D inhibitory activities.