Fragment-based design of selective GPCR ligands guided by free energy simulations.

Pierre Matricon,Kenneth A Jacobson,Jens Carlsson,Duc Duy Vo,Jan Kihlberg,Zhan-Guo Gao

doi:10.1039/d1cc03202j

Abstract

Fragment-based drug discovery relies on successful optimization of weakly binding ligands for affinity and selectivity. Herein, we explored strategies for structure-based evolution of fragments binding to a G protein-coupled receptor. Molecular dynamics simulations combined with rigorous free energy calculations guided synthesis of nanomolar ligands with up to >1000-fold improvements of binding affinity and close to 40-fold subtype selectivity.

Highlights

Pierre Matricon, a Duc Duy Vo,a Zhan-Guo Gao,b Jan Kihlberg, c Kenneth A
Molecular dynamics simulations combined with rigorous free energy calculations guided synthesis of nanomolar ligands with up to 41000-fold improvements of binding affinity and close to 40-fold subtype selectivity
Several recent studies suggest that relative binding free energies calculated from molecular dynamics (MD) simulations can guide hitto-lead optimization for important drug targets such as G protein-coupled receptors (GPCRs).[7,8,9]

Summary

Introduction

Pierre Matricon, a Duc Duy Vo,a Zhan-Guo Gao,b Jan Kihlberg, c Kenneth A. Molecular dynamics simulations combined with rigorous free energy calculations guided synthesis of nanomolar ligands with up to 41000-fold improvements of binding affinity and close to 40-fold subtype selectivity. Several recent studies suggest that relative binding free energies calculated from molecular dynamics (MD) simulations can guide hitto-lead optimization for important drug targets such as G protein-coupled receptors (GPCRs).[7,8,9]

Results

Conclusion