Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs

Congreve, Miles; Oswald, Christine; Marshall, Fiona H.

doi:10.1016/j.tips.2017.05.010

Cited by 123Receptor Mechanisms and SignalingComputational Drug Discovery MethodsNeuroscience and Neuropharmacology Research

Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs

Congreve, Miles, Oswald, Christine, Marshall, Fiona H.·2017·Trends in Pharmacological Sciences

DOI 10.1016/j.tips.2017.05.010

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Abstract

Structural insights have been revealed from X-ray co-complexes of a range of G protein-coupled receptors (GPCRs) and their allosteric ligands. The understanding of how small molecules can modulate the function of this important class of receptors by binding to a diverse range of pockets on and inside the proteins has had a profound impact on the structure-based drug design (SBDD) of new classes of therapeutic agents. The types of allosteric pockets and the mode of modulation as well as the advantages and disadvantages of targeting allosteric pockets (as opposed to the natural orthosteric site) are considered in the context of these new structural findings.

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Initial efforts focused on developing orthosteric inhibitors that target active site endogenous ligands, but the selectivity of these inhibitors has been hindered by the high conservation of orthosteric binding sites in GPCRs.
“While initial efforts have focused on developing orthosteric inhibitors that target active site endogenous ligands (orthosteric site), the selectivity of these inhibitors has been hindered by the high conservation of orthosteric binding sites in GPCRs.296,297”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [296]

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Authors: Congreve, M., Oswald, C., & Marshall, F. H.
Affiliations: Heptares Therapeutics (United Kingdom) (GB)
Corresponding author: Marshall, Fiona H.
ORCID: Congreve, Miles
Marshall, Fiona H.
Venue: Trends in Pharmacological Sciences
Publisher: Elsevier BV
Published: 2017-09
Volume: 38
Issue: 9
Pages: 837-847
ISSN: 0165-6147 (ISSN-L)
DOI: 10.1016/j.tips.2017.05.010
OpenAlex: W2642015544
Cited by: 123
References: 52
Citations by year: 2026: 4 · 2025: 9 · 2024: 7 · 2023: 16 · 2022: 12 · 2021: 17 · 2020: 14 · 2019: 23 · 2018: 19 · 2017: 2
FWCI: 1.51
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Trends in Pharmacological Sciences (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: structure-based drug design, G protein-coupled receptors, allosteric modulators, allosteric pocket, orthosteric binding site, allosteric modulation, small-molecule ligands
MeSH terms: Binding Sites, Humans, Ligands, Structure-Activity Relationship, Drug Design, Crystallography, X-Ray, Receptors, G-Protein-Coupled

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Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs

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