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- W4319936480 abstract "The Kristen Rat Sarcoma (KRAS) protein, encoded by the KRAS gene, is a signal transducer that plays a crucial role in regulating cell proliferation. KRAS mutations have been known to cause lung, colorectal, and pancreatic cancers. Previously, KRAS was considered an undruggable target. However, with a better understanding of the protein's biology paired with advanced new technologies, the FDA approved the first KRAS inhibitor (sotorasib) for lung cancer patients with the KRASG12C mutation in 2021, expressing the recent interest of targeted drugs for KRAS. Oncogenic KRAS requires activation by the guanine nucleotide exchange factor (GEF) Son of Sevenless 1 (SOS1). The goal of this study is to develop novel pan-KRAS inhibitors by targeting the KRAS-SOS1 interactions through computational modeling. To start, we applied Gaussian accelerated molecular dynamics (GaMD) simulation, an advanced conformational sampling method, to collect the nature of the KRAS protein motion in solution. Then, the clustering analysis method was used to assemble KRAS conformational structures into ten groups. Finally, virtual screening and docking simulations are performed using the ChemBridge molecule database to identify potential KRAS inhibitors and their binding locations. We have addressed 60 compounds that show a good binding score to KRAS for a later experimental assessment of their (1) ability to disrupt the KRAS-SOS1 interactions and (2) cytotoxicity in KRAS mutation-bearing cell lines. The work provides insights into the drug efficacy of KRAS inhibitors and gives rise to a novel set of KRAS candidates to be used in oncogenic clinical treatments." @default.
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- W4319936480 date "2023-02-01" @default.
- W4319936480 modified "2023-09-25" @default.
- W4319936480 title "Identification of novel inhibitors targeting KRAS-SOS1 interactions by structure-based drug design" @default.
- W4319936480 doi "https://doi.org/10.1016/j.bpj.2022.11.1133" @default.
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