What can we learn from molecular dynamics simulations for GPCR drug design?

Abstract

Recent years have seen a tremendous progress in the elucidation of experimental structural information for G-protein coupled receptors (GPCRs). Although for the vast majority of pharmaceutically relevant GPCRs structural information is still accessible only by homology models the steadily increasing amount of structural information fosters the application of structure-based drug design tools for this important class of drug targets. In this article we focus on the application of molecular dynamics (MD) simulations in GPCR drug discovery programs. Typical application scenarios of MD simulations and their scope and limitations will be described on the basis of two selected case studies, namely the binding of small molecule antagonists to the human CC chemokine receptor 3 (CCR3) and a detailed investigation of the interplay between receptor dynamics and solvation for the binding of small molecules to the human muscarinic acetylcholine receptor 3 (hM3R).

Keywords

• Molecular dynamics simulations
• GPCR
• Homology modeling
• Water network
• CC chemokine receptor 3
• Muscarinic acetylcholine receptor 3