Discovery of Potential KRAS‐SOS1 Inhibitors from South African Natural Compounds: An In silico Approach

Abstract

For decades the direct targeting of KRAS as a driver of non‐small cell lung cancer, colorectal and pancreatic cancers as well as the inhibition of the RAF‐MEK‐ERK pathway has shown little success due to feedback networks that keep the pathway in control. Inhibiting SOS1, a KRAS activator, has therefore become a promising escape route to treating KRAS‐driven cancers. The search for SOS1 inhibitors has since gained momentum although no drug has been approved yet. Owing to the time‐consuming and difficult processes that characterize the discovery and approval of drugs, natural products have become useful in addressing the unmet medical needs. In this study we employed computational techniques to screen South African natural products for inhibitors with the potential to inhibit SOS1‐KRAS activation. In this study, eight natural compounds, from plants and marine life, possessing antineoplastic activities with good docking and ADMET properties were identified. These compounds, viz., SANCDB00219, SANCDB0290, SANCDB00369, SANCDB00416, SANCDB00421, SANCDB00749, SANCDB00957 and SANCDB001124 exhibited favorable total free binding energies in complex with SOS1‐KRAScharacterized by conventional and carbon hydrogen bonds, van der Waals, pi‐alkyl and pi‐sigma interactions with the binding site residues. It was further revealed that these compounds induced conformational stability on the structural architecture of SOS1‐KRAS, and decreased the structural flexibility of its individual C‐α atoms as a mechanism of inhibition. Upon experimental validation, these compounds from a natural origin could serve as lead identification of small molecules to address SOS1‐KRAS associated diseases.

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