Docking of virtual libraries identifies small-molecule agonists of neurotensin receptors with analgesic activity
Year: 2026
Type: article
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.
Source: Nature Communications
Authors: Nicolas Panel, Duy Duc Vo, Harald Hübner, Mattia Deluigi, Szymon Pach, Félix Bélair, Dorothee Weikert, Christoph Klenk, Mark Hilge, Niharika Shiva, Isabelle Brochu, Jean-Michel Longpré, Frida Bällgren, Aljona Saleh, Huabin Hu, Jon Kapla, Stefanie Kampen, Israel Cabeza de Vaca, Jan Kihlberg, Nina Wettschureck, Philippe Sarret, Andreas Plückthun, Peter Gmeiner, Jens Carlsson
Institutions: Uppsala University, Science for Life Laboratory, Friedrich-Alexander-Universität Erlangen-Nürnberg, University of Zurich, Université de Sherbrooke, Institut de pharmacologie de Sherbrooke, Justus-Liebig-Universität Gießen, Max Planck Institute for Heart and Lung Research, Goethe University Frankfurt
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funder: European Commission
OpenAlex ID: W7170068873