Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity

被引:150
作者
Kaplan, Anat Levit [1 ]
Confair, Danielle N. [2 ]
Kim, Kuglae [3 ,4 ]
Barros-Alvarez, Ximena [5 ]
Rodriguiz, Ramona M. [6 ,7 ]
Yang, Ying [1 ]
Kweon, Oh Sang [2 ]
Che, Tao [8 ]
McCorvy, John D. [9 ]
Kamber, David N. [2 ]
Phelan, James P. [2 ]
Martins, Luan Carvalho [1 ,10 ]
Pogorelov, Vladimir M. [6 ]
DiBerto, Jeffrey F. [3 ]
Slocum, Samuel T. [3 ]
Huang, Xi-Ping [11 ]
Kumar, Jain Manish [3 ]
Robertson, Michael J. [5 ]
Panova, Ouliana [5 ]
Seven, Alpay B. [5 ]
Wetsel, Autumn Q. [6 ]
Wetsel, William C. [6 ,7 ,12 ,13 ]
Irwin, John J. [1 ]
Skiniotis, Georgios [5 ]
Shoichet, Brian K. [1 ]
Roth, Bryan L. [3 ,14 ]
Ellman, Jonathan A. [2 ]
机构
[1] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA
[2] Yale Univ, Dept Chem, New Haven, CT 06520 USA
[3] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27515 USA
[4] Yonsei Univ, Dept Pharm, Incheon, South Korea
[5] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA
[6] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27706 USA
[7] Duke Univ, Med Ctr, Mouse Behav & Neuroendocrine Anal Core Facil, Durham, NC 27706 USA
[8] Washington Univ, Sch Med, Ctr Clin Pharmacol, Dept Anesthesiol, St Louis, MO USA
[9] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA
[10] Univ Fed Minas Gerais, Inst Biol Sci, Biochem Dept, Belo Horizonte, MG, Brazil
[11] Univ N Carolina, Sch Med, Natl Inst Mental Hearth Psychoact Drug Screening, Chapel Hill, NC 27515 USA
[12] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA
[13] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA
[14] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27515 USA
关键词
FREE-ENERGY; PSILOCYBIN TREATMENT; DRUG DISCOVERY; SEROTONIN; LIGANDS; SELECTIVITY; ANXIETY; ACTIVATION; PREDICTION; FEATURES;
D O I
10.1038/s41586-022-05258-z
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR 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-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. 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-HT2AR 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.
引用
收藏
页码:582 / +
页数:36
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