ArticleScience advances2025
Discovering cryptic pocket opening and binding of a stimulant derivative in a vestibular site of the 5-HT
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Who cites it
6 citing papers in PubMed.
- Review
- Biophysical insights into a cryptic ligand site in the hydrophobic core of human PCNA.Biophysical journal · 2026Article
- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- Decrypting cryptic pockets with physics-based simulations and artificial intelligence.Current opinion in structural biology · 2026Review
- Molecular dynamics simulation in traditional Chinese medicine research: from molecular mechanisms to multiscale validation.Frontiers in chemistry · 2026Review
- Integrated computational and experimental identification ofFrontiers in chemistry · 2025Article
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A diverse set of modulators, including stimulants and anesthetics, regulates ion channel function in our nervous system. However, structures of ligand-bound complexes can be difficult to capture by experimental methods, particularly when binding is dynamic. Here, we used computational methods and electrophysiology to identify a possible bound state of a modulatory stimulant derivative in a cryptic vestibular pocket of a mammalian serotonin-3 receptor. We first applied a molecular dynamics simulation-based goal-oriented adaptive sampling method to identify possible open-pocket conformations, followed by Boltzmann docking that combines traditional docking with Markov state modeling. Clustering and analysis of stability and accessibility of docked poses supported a preferred binding site; we further validated this site by mutagenesis and electrophysiology, suggesting a mechanism of potentiation by stabilizing intersubunit contacts. Given the pharmaceutical relevance of serotonin-3 receptors in emesis, psychiatric, and gastrointestinal diseases, characterizing relatively unexplored modulatory sites such as these could open valuable avenues to understanding conformational cycling and designing state-dependent drugs.
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Registered trials
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