New Compounds Identified for ROS1 G2032R Mutation

A recent computational study has identified four small molecules that may inhibit the crizotinib-resistant ROS1 G2032R mutation found in non-small-cell lung cancer (NSCLC). Resistance to ROS1-targeted therapies, such as crizotinib, poses a major challenge in the treatment of ROS1-positive tumors, particularly in cases where the G2032R mutation is present.

Researchers used a homology model based on PDB ID 7Z5X to construct a full-length structure of the mutated ROS1 protein. A virtual screen of 1,760 compounds from the PubChem database identified four candidates—PubChem CIDs 67463531, 72544946, 139431449, and 139431487—that demonstrated higher binding affinity than crizotinib and met drug-likeness criteria.

Molecular docking showed that the selected compounds had XP Gscores ranging from −9.68 to −11.24 kcal/mol, compared with −7.50 kcal/mol for crizotinib. The top-scoring compound, 67463531, formed key hydrogen bonds with Met2029 and Asp2033. MD simulations over 500 nanoseconds confirmed the structural stability of the protein–ligand complexes, particularly for 67463531 and 72544946.

All four compounds conformed to Lipinski’s Rule of Five and showed favorable predicted absorption, distribution, metabolism, and excretion (ADME) profiles, including oral absorption rates between 77% and 92%.

Density functional theory (DFT) calculations further supported the drug-like characteristics of the identified compounds, with energy gaps and electronic descriptors comparable to crizotinib.

The study concludes that these compounds warrant further evaluation as potential inhibitors of ROS1 G2032R and may inform the development of targeted therapies for resistant forms of ROS1-driven NSCLC.