From byte to bench to bedside: Structure-based drug design targeting the full-length human antigen R (HuR) protein using molecular docking and dynamics simulations

The interaction between RNA and RNA-binding proteins (RBPs) is fundamental to mRNA processing and maturation, and they are also implicated in tumor development. Therefore, it is crucial to thoroughly understand the full-length structure and functions of these proteins, as well as identifying and developing new potential candidate inhibitors against them. We identified promising inhibitor candidates through a comprehensive structure-based drug design workflow that combined high-throughput virtual screening, molecular docking, molecular dynamics simulations and MM/PBSA free energy. Our screening process included libraries of small molecules based on natural products, small anti-cancerous molecules, and RNA-protein interaction inhibitors along with a pre-identified known inhibitor served as the control molecule throughout our investigation. The selection process has involved evaluating the compounds according to their pharmacokinetic parameters, Lipinski's Rule of Five compliance, predicted inhibition constant (Ki), estimated ligand efficiency, and estimated free binding energy (ΔG). Additionally, we assessed how the compounds positioned within the active site, the number and types of intermolecular non-covalent interactions, and identified the participating amino acid residues. Following comprehensive binding analysis, we selected twelve promising molecules, along with known inhibitor, to study via MD simulations and examining how these compounds influence HuR structural stability and conformational behavior. According to the results of both MD simulation analyses and MM/PBSA free energy calculation, the following candidate inhibitors are reported and recommended for further experimental studies, ranked by their overall stability and binding affinity (derived from all energy components) towards HuR protein: M007-0287 > 7287-0165 > D103-1163 > ZINC05415104 > ZINC05415099 > PubChem5316743 (control).