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The CCPBioSim Industry Talk in May will be given by Ijen Chen of Nxera. The talk will be online at 2pm UK time on Wednesday 27 May.
Registration is free - click here to get the MSTeams webinar link!
Title: Mapping GPCR Allostery: Translating PDB Insights into Design Decisions
Abstract:
Allosteric modulation remains one of the most promising yet underdelivered strategies in G protein-coupled receptor (GPCR) drug discovery. The potential to tune selectivity, bias signalling, and avoid orthosteric competition is well established. The clinical record is not. Two problems sit at the heart of this. First, GPCR allosteric pockets are conformationally plastic and state-dependent, offering none of the geometric stability conventional SAR logic requires. Second, binding-site naming remains inconsistent across receptors and publications, making cross-receptor comparison unreliable and cross-publication learning nearly impossible. Without a shared reference frame, design strategies are reinvented rather than refined, and method development cannot build on what came before.
This talk addresses both problems directly. I describe a standardised annotation of GPCR allosteric sites derived from structural evidence across the Protein Data Bank. Systematic analysis exposes recurring site classes and their chemical preferences, and reveals where common pocket-detection approaches fail and why. These failure modes motivate targeted improvements to pocket detection, yielding more reliable identification and characterisation of allosteric pockets for structure-based design. I close with design examples that ground specific decisions in structural and mechanistic context.
