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Abstract
Kristen rat sarcoma (KRAS) is an oncogene responsible for almost 20% of all human cancers and over 90% of pancreatic ductal adenocarcinoma. To date, only two covalent drugs are approved by the United States food and drug administration (FDA) for the treatment of KRAS G12C related cancers. However, their effectiveness is limited in cancers driven by non-G12C KRAS mutations as they rely on covalent bonding to the mutant Cys12. On top of that, the emergence of resistance to allele-specific inhibitors has shifted substantial effort toward developing noncovalent KRAS inhibitors. As a result, several noncovalent inhibitors are in clinical trials, yet none has been approved for market use, underscoring the need for new inhibitors. In this study, we reported small molecules that show a promising micromolar anti-proliferation activity against pancreatic cancer cell lines. The investigated compounds are mainly amine-containing heterocycles with scaffolds that are distinct from those found in existing drugs or lead molecules.The molecules were identified through a structure-based drug design campaign on a physicochemically tailored 3D ligand library against switch II pocket of KRAS mutants. Based on their micromolar activity, extensive interactions in predicted binding modes, and analyses of structural and physicochemical features, we propose that these active hits can serve as a starting point for the future characterization and optimization of pan-KRAS inhibitors with broad efficacy. Moreover, our work demonstrates the proof of concept for using virtual screening in noncovalent drug discovery to benefit from abundant 3D structures of drug-like molecules and the growing database of experimental protein structures, especially when computational resources are limited.
Keywords: KRAS drug discovery, virtual screening, molecular docking, cell growth assay
- Correspondence to: amanuel.getahun@bdu.edu.et
