In Silico Identification of Putative Allosteric Pockets and Inhibitors for the KRASG13D-SOS1 Complex in Cancer...

Area of Science:

• Oncology
• Structural Biology
• Computational Chemistry

Background:

• RAS mutations are prevalent in human cancers, driving tumor growth through enhanced signaling pathways.
• KRAS is a key oncogene frequently mutated in lung, pancreatic, and colorectal cancers.
• Directly targeting KRAS is challenging; however, its interaction with Son of Sevenless (SOS) 1 presents a viable therapeutic target.

Purpose of the Study:

• To identify novel allosteric binding sites on the SOS1 protein, particularly in complex with KRAS.
• To screen natural compounds for their potential to inhibit KRAS-SOS1 interactions.
• To evaluate the efficacy of identified compounds in disrupting the KRAS-SOS1 complex.

Main Methods:

• Utilized network-based models (essential site scanning, residue interaction network) to reveal allosteric binding sites in KRAS-SOS1 complexes.
• Screened the InterBioScreen (IBS) database against identified pockets using Glide docking.
• Performed molecular dynamics (MD) simulations and MM-GBSA calculations to assess binding free energy and stability of hit compounds.

Main Results:

• Identified two novel allosteric pockets in the KRASG13D-SOS1 complex.
• Screening yielded seven hit compounds with anti-cancer properties and persistent interactions with key residues.
• STOCK1N-09823 emerged as the most promising compound, disrupting critical R73/N879 and R73/Y884 interactions essential for SOS1-mediated KRAS activation.

Conclusions:

• The study successfully identified novel allosteric sites on SOS1 for potential therapeutic intervention in RAS-driven cancers.
• STOCK1N-09823 demonstrates significant potential as an inhibitor by disrupting the KRAS-SOS1 interaction crucial for oncogenic signaling.
• These findings offer a promising new avenue for developing targeted therapies against KRAS-mutated cancers.