Studying an NRAS-NRAS interface for Drug Discovery

Harshitha Muddamsetty

Mentor: Dr. Trent Balius, Cancer Research Technology Program, Frederick National Lab for Cancer Research.

Date/Time: December 10th, 2024 at 12:00pm.

Abstract: The RAS isoforms (KRAS, HRAS, and NRAS) exhibit distinct cancer type-specific profiles, with NRAS mutations being the second most prevalent RAS mutations in skin and hematological malignancies. While extensive studies have focused on K- and H-RAS mutations, NRAS mutations, particularly Q61K and Q61R, remain relatively less explored despite their significant roles in cancer. Recent structural studies of the NRAS Q61K mutant in the GTP-bound form have revealed a novel pocket near switch II, induced by ligand binding to the active form of the protein. This previously unseen pocket presents a promising opportunity for developing inhibitors targeting mutant NRAS.

During my internship, We focused on leveraging these insights to study the NRAS dimer interfaces and their potential as druggable targets. Using the NRAS Q61K structure (PDB code 8VM2), we used AMBER software suite to perform MMGBSA (Molecular Mechanics Generalized Born Surface Area) single-point energy calculations to assess the energies and stability of the NRAS dimer complex and compared it to individual monomers to calculate the strain energy. To further explore the dynamics and stability of the dimer interface, we conducted 10-nanosecond molecular dynamics simulations in triplicate on both the complex and the monomers.

Additionally, we utilized DOCK 6 for virtual screening of ~8 million small molecules from the ZINC22 in-stock library to identify compounds capable of binding to and stabilizing the NRAS dimer interface. This work has laid a foundation for prioritizing molecules for experimental validation and further structural studies.