FMOPhore for hotspot identification and efficient fragment-to-lead growth strategies.

Abstract

Fragment based drug design is like a chess game in that a good or a bad move can dramatically influence the outcome. In the design process, it is important to identify the key binding site residues (hotspots) that can have a substantial impact on ligand potency and efficiency. Here, we introduce FMOPhore algorithm represented with a scoring function named FP-score, which combines Quantum Mechanics Fragment Molecular Orbital calculations with 3D-protein-ligand pharmacophore models. FP-score accurately classifies binding site residues in two classes: 1) Hotspot residues (Delineated into three categories; Anchor, Transient, and Accessible) and 2) non-hotspot residues. We apply our algorithm in two different scenarios: holo-complex and apo-structure, testing its robustness on 46 different protein targets including an experimental case study on drug-resistance hotspots across 829 protein-ligand complexes. We handle protein binding site flexibility using Dy-FMOPhore which improves the detection of hotspots. FMOPhore provides valuable insight for efficient, selective fragment growing and lead optimization strategies.