Drug Discovery

Computational Medicinal Chemistry Approaches for GPCR Structure-Based Drug Discovery

By Juan Carlos Mobarec | Sep 10, 2019


20th SCI / RSC Medicinal Chemistry Symposium

8 – 11 September 2019

Cambridge, UK

SCI, Royal Society of Chemistry

Poster Summary

An increasing number of cryo-EM and X-ray crystal structures of GPCR-ligand complexes continue to reveal previously unknown ligand binding sites. Furthermore, emerging sets of GPCR crystal structures of multiple diverse ligands bound to closely related receptors enable a protein-structure based view of how different ligands bind this major drug target class.

From the analysis of GPCR structures we gather several important learnings and repercussions for computational medicinal chemistry design that should be transferable and relevant for many targets, including:

A) The important roles of lipophilic hot spots and water networks as drivers of GPCR druggability, ligand binding, and selectivity

B) Diverse binding modes of similar ligands across the structural GPCRome

C) Caveats when using pharmacophore-based similarity principles for modeling receptor-ligand complexes with different ligand chemotypes

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