The Ras protein family (including N-Ras, H-Ras, and K-Ras isoforms) consists of small GTPases acting as an on/off switch (GTP-bound active, GDP-bound inactive) and plays roles in cellular functions such as signal transduction, cell division, and differentiation. First 80 amino acids of G-domain on their structures are conserved in homologous proteins and contain Switch I and Switch II regions to which Ras effectors bind. The oncogenic mutations, occurring in 30% of human cancers, may block Ras in its active state and continuously activate downstream signaling pathways, causing lung, colorectal, and pancreatic cancers. The KRAS gene is responsible for about 85% of Ras mutations. Recent studies have shown promising results in targeting G12C mutant K-Ras with small-molecule drugs (Adagrasib and Sotorasib, the first molecule to receive accelerated FDA approval) which are designed to covalently bind to the mutated 12th amino acid (Glycine), near the Switch II region stabilizing K-Ras in its inactive state. The purpose of this study is to analyze all available experimental K-Ras structures to create a seed for the library of molecules similar to G12C mutant K-Ras covalent inhibitors and to determine the best drug candidates by virtual screening with covalent docking. For this aim, the set of reactive molecules (11,429,395) obtained from the ZINC database was subjected to a virtual screening workflow created in the KNIME program. The 3-dimensional similarities between Lipinski's rule-of-five applied molecules and the positive control molecules were determined. Finally, 129 molecules obtained after virtual screening were covalently docked using Flare software, and 2 molecules with a higher score than the positive controls were discovered as drug candidates. (This study is supported by the TUBITAK 2209-A Project. Application number: 1919B012220712, ORCID NO: 0009-0008-4698-7505, 0000-0003-2359-2267, 0000-0003-0336-0645"
Anahtar Kelimeler: KRAS, G12C, Inhibitor, Covalent Docking, Virtual Screening, Cancer
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