G-protein-coupled receptors (GPCRs) represent the primary targets of about one third of currently marketed drugs. However, GPCR drug discovery has suffered from major challenges, including the inherent flexibility of the receptors and the toxicity of agonist and antagonist drugs that are designed to bind the conserved “orthosteric” site. Here, we have implemented a unique structure-based approach to design allosteric modulators as selective drug leads of the M2 muscarinic GPCR. All-atom accelerated molecular dynamics simulations were performed to construct structural ensembles that account for the receptor flexibility. Through iterative molecular docking and experimental testing, half of the 38 computationally selected lead compounds showed allosteric activity at the M2 muscarinic receptor. Our method successfully identified both positive and negative allosteric modulators of the M2 receptor with unprecedented chemical diversity and outstanding potential for further structure-activity relationship studies. This approach shall be of wide applicability for drug discovery of many other GPCRs.

Computer-aided discovery of allosteric modulators for a muscarinic G-protein-coupled receptor

253rd National Meeting (2017)

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