A Computational Foundation Toward Targeting the ELMO1/DOCK2 Complex

Abstract

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.