Docking of virtual libraries identifies small-molecule agonists of neurotensin receptors with analgesic activity

Abstract Peptide-activated G protein-coupled receptors (GPCRs) play crucial roles in numerous diseases, but remain difficult therapeutic targets due to the challenges in developing small-molecule drugs. Here, we explore structure-based strategies to identify small-molecule agonists of neurotensin (NTS) receptors, which hold promise for developing non-opioid analgesics. Chemical libraries of drug-like molecules are first designed based on a receptor-peptide complex, and then 14.5 million compounds are computationally docked to the orthosteric binding site of the NTS 1 receptor. A set of 39 top-ranked compounds is synthesized, and seven of these are experimentally confirmed to activate the NTS 1 receptor. Structure-guided optimization yields NTS 1 ligands with signaling signatures distinct from the endogenous peptide, and these compounds also exhibit high affinity for the NTS 2 receptor. High-resolution crystal structures of two agonists bound to the NTS 1 receptor confirm predicted binding modes and reveal key determinants of activation. In vivo, the compounds produce robust antinociception in rodents without inducing hypotension, consistent with a contribution of NTS 2 receptor activity. To facilitate broader application of our virtual screening approach to peptide-binding GPCRs, we provide access to tailored chemical libraries containing billions of readily synthesizable compounds.

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Publication Details

Journal
Nature Communications
Published
2026-07-22
DOI
https://doi.org/10.1038/s41467-026-74990-1
Primary Topic
Neuropeptides and Animal Physiology
Type
article
Field-Weighted Citation Impact
0.00
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article

Docking of virtual libraries identifies small-molecule agonists of neurotensin receptors with analgesic activity

Mattia Deluigi, Philippe Sarret, Christoph Klenk, Niharika Shiva et al.
Nature Communications
Neuropeptides and Animal Physiology
article

Docking of virtual libraries identifies small-molecule agonists of neurotensin receptors with analgesic activity

Mattia Deluigi, Philippe Sarret, Christoph Klenk, Niharika Shiva, Israel Cabeza de Vaca, Dorothée Weikert, Stefanie Kampen, Nina Wettschureck, Jon Kapla, Jan Kihlberg, Duy Duc Vo, Szymon Pach, Nicolas Panel, Jens Carlsson, Peter Gmeiner, Andreas Plückthun, Jean‐Michel Longpré, Harald Hübner, Aljona Saleh, Frida Bällgren, M. Hilge, Huabin Hu, Isabelle Brochu, Félix Bélair
article en

Abstract

Abstract Peptide-activated G protein-coupled receptors (GPCRs) play crucial roles in numerous diseases, but remain difficult therapeutic targets due to the challenges in developing small-molecule drugs. Here, we explore structure-based strategies to identify small-molecule agonists of neurotensin (NTS) receptors, which hold promise for developing non-opioid analgesics. Chemical libraries of drug-like molecules are first designed based on a receptor-peptide complex, and then 14.5 million compounds are computationally docked to the orthosteric binding site of the NTS 1 receptor. A set of 39 top-ranked compounds is synthesized, and seven of these are experimentally confirmed to activate the NTS 1 receptor. Structure-guided optimization yields NTS 1 ligands with signaling signatures distinct from the endogenous peptide, and these compounds also exhibit high affinity for the NTS 2 receptor. High-resolution crystal structures of two agonists bound to the NTS 1 receptor confirm predicted binding modes and reveal key determinants of activation. In vivo, the compounds produce robust antinociception in rodents without inducing hypotension, consistent with a contribution of NTS 2 receptor activity. To facilitate broader application of our virtual screening approach to peptide-binding GPCRs, we provide access to tailored chemical libraries containing billions of readily synthesizable compounds.

Nature CommunicationsVol. 17(1)
Goethe University Frankfurt (DE), Uppsala University (SE), Université de Sherbrooke (CA), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Justus-Liebig-Universität Gießen (DE), University of Zurich (CH), Science for Life Laboratory (SE), Max Planck Institute for Heart and Lung Research (DE), Comprehensive Cancer Center Erlangen (DE)
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Openalex Percentile: Top 13%
Neuropeptides and Animal Physiology
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