Discovery of Potential GPRC5D Inhibitors through Virtual Screening and Molecular Dynamics Simulations

Abstract

G protein-coupled receptor family C, group 5, member D (GPRC5D), a member of the G protein-coupled receptor (GPCR) family, has recently emerged as a promising target for immunotherapy in hematologic malignancies, particularly multiple myeloma. However, no systematic virtual screening studies have been conducted to identify small-molecule inhibitors targeting GPRC5D. To address this gap, a multistep computational screening strategy is developed that integrates Protein−Ligand Affinity prediction NETwork (PLANET), a GPU-accelerated version of AutoDock Vina (Vina-GPU), molecular mechanics/generalized born surface area (MM/GBSA), and an online tool for Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) property prediction (admetSAR 3.0), complemented by molecular dynamics (MD) simulations and absolute binding free energy (ABFE). From an initial library of 8,617 compounds, four candidates (compounds 1, 2, 7, and 8) are prioritized. Among them, compound 2 shows relatively strong binding affinity (MM/GBSA ΔG = −79.8 kcal mol−1, ABFE = −9.0 kcal mol−1) and high drug-likeness (quantitative estimate of drug-likeness = 0.670). MD simulations confirm its stable salt bridge interactions with key residues ASP238 and ASP239. This study proposes a systematic virtual screening workflow to facilitate the discovery of GPRC5D-targeted therapeutics.