G protein-coupled receptors (GPCRs) are an important and long-standing family of drug targets. Despite many success stories, today there are still a significant number of GPCRs with compelling pre-clinical validation that remain highly challenging for drug discovery. Over the last 10 years there has been substantial progress in the structural biology of GPCRs facilitating Structure-Based Drug Design (SBDD) approaches. Sosei Heptares uses its proprietary StaR® technology to thermostabilise GPCRs by mutagenesis into a chosen conformational state. These purified proteins can then be used for biophysical screening techniques and crystallisation to yield X-ray structures with multiple ligands.<br/><br/>Using the StaR® approach, Sosei Heptares has solved structures of many GPCRs, in several cases leading to the identification of allosteric binding sites. These structures highlight the diversity of GPCR binding sites and reveal a much greater variety of ligand binding modes and positions than might have been expected. Amongst these more recent structures, several small molecule allosteric binding sites at the GPCR-membrane interface have been identified. This presentation will discuss both the new opportunities and challenges these binding sites present in drug design for GPCR targets.<br/><br/>A review of the ‘drugability’ of these receptor-lipid binding sites using detailed computational analysis together with an overview of the physicochemical properties of ligands known to bind these sites will be presented. Case studies describing the medicinal chemistry challenges of balancing typical high lipophilicity with the desired pharmacological and ADME profile will also be discussed. Finally, a perspective on what successful design strategies can be considered to maximise success in this challenging space will be discussed.

Impact of GPCR structure-based drug discovery on identification and optimisation of allosteric modulators that bind at the receptor-membrane interface

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.