Bespoke library docking for 5-HT 2A receptor agonists with antidepressant activity.

Autor: Kaplan AL; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA., Confair DN; Department of Chemistry, Yale University, New Haven, CT, USA., Kim K; Department of Pharmacology, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC, USA.; Department of Pharmacy, Yonsei University, Incheon, Republic of Korea., Barros-Álvarez X; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Rodriguiz RM; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA., Yang Y; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA., Kweon OS; Department of Chemistry, Yale University, New Haven, CT, USA., Che T; Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA., McCorvy JD; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA., Kamber DN; Department of Chemistry, Yale University, New Haven, CT, USA., Phelan JP; Department of Chemistry, Yale University, New Haven, CT, USA., Martins LC; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.; Biochemistry Department, Institute for Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil., Pogorelov VM; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA., DiBerto JF; Department of Pharmacology, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC, USA., Slocum ST; Department of Pharmacology, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC, USA., Huang XP; National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC, USA., Kumar JM; Department of Pharmacology, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC, USA., Robertson MJ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Panova O; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Seven AB; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Wetsel AQ; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA., Wetsel WC; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA. william.wetsel@duke.edu.; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA. william.wetsel@duke.edu.; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA. william.wetsel@duke.edu.; Department of Neurobiology, Duke University Medical Center, Durham, NC, USA. william.wetsel@duke.edu., Irwin JJ; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA. jji@cgl.ucsf.edu., Skiniotis G; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu., Shoichet BK; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA. bshoichet@gmail.com., Roth BL; Department of Pharmacology, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina Chapel Hill, Chapel Hill, NC, USA. bryan_roth@med.unc.edu., Ellman JA; Department of Chemistry, Yale University, New Haven, CT, USA. jonathan.ellman@yale.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Oct; Vol. 610 (7932), pp. 582-591. Date of Electronic Publication: 2022 Sep 28.
DOI: 10.1038/s41586-022-05258-z
Abstrakt: There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally 1-4 . Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization 5-7 . Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT 2A receptor (5-HT 2A R) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT 2A or the 5-HT 2B receptors. Structure-based optimization led to the 5-HT 2A R agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT 2A R agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT 2A R. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT 2A R agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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