A Computational Foundation Toward Targeting the ELMO1/DOCK2 Complex

Engulfment and Cell Motility protein 1 (ELMO1) regulates cell migration, phagocytosis, and cytoskeletal remodeling, positioning it as a compelling therapeutic target across kidney diseases, oncology, enteric infections and inflammation. Despite this potential, no approved therapeutics or clinically validated small-molecule modulators of ELMO1 currently exist. ELMO1 functions by forming a complex with DOCK180 (or DOCK2) to activate the small GTPase Rac1, and the recent structural resolution of the ELMO1/DOCK2 complex now provides an opportunity to target this protein-protein interface directly. Here, we present the first investigation into the druggability of the ELMO1/DOCK2 complex and report the initial virtual screening to identify small-molecule inhibitors of this interaction. Molecular dynamics (MD) and free energy level (FEL) studies were carried out to validate the potential of the predicted hits. This work establishes a computational framework for the development of the first generation of ELMO1-targeted therapeutics. In addition to demonstrating the drugability of ELMO1, this work introduces two open-source Python tools for the rapid analysis and visualization of protein-protein interaction and ligand-protein MD trajectories from DESMOND output files. These tools are designed to be broadly accessible, offering practical utility to the wider DESMOND user community.