Identification of natural products as novel ligands for the human 5-HT<sub>2C</sub> receptor

Yao Peng; Simeng Zhao; Yiran Wu; Haijie Cao; Yueming Xu; Xiaoyan Liu; Wenqing Shui; Jianjun Cheng; Suwen Zhao; Ling Shen; Jun Ma; Ronald J. Quinn; Raymond C. Stevens; Guisheng Zhong; Zhi-Jie Liu

doi:10.1007/s41048-018-0047-1

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Article Navigation > Biophysics Reports > 2018 > 4(1): 50-61

Yao Peng, Simeng Zhao, Yiran Wu, Haijie Cao, Yueming Xu, Xiaoyan Liu, Wenqing Shui, Jianjun Cheng, Suwen Zhao, Ling Shen, Jun Ma, Ronald J. Quinn, Raymond C. Stevens, Guisheng Zhong, Zhi-Jie Liu. Identification of natural products as novel ligands for the human 5-HT2C receptor. Biophysics Reports, 2018, 4(1): 50-61. doi: 10.1007/s41048-018-0047-1

Citation:

Yao Peng, Simeng Zhao, Yiran Wu, Haijie Cao, Yueming Xu, Xiaoyan Liu, Wenqing Shui, Jianjun Cheng, Suwen Zhao, Ling Shen, Jun Ma, Ronald J. Quinn, Raymond C. Stevens, Guisheng Zhong, Zhi-Jie Liu. Identification of natural products as novel ligands for the human 5-HT_2C receptor. Biophysics Reports, 2018, 4(1): 50-61. doi: 10.1007/s41048-018-0047-1

Citation:

Yao Peng, Simeng Zhao, Yiran Wu, Haijie Cao, Yueming Xu, Xiaoyan Liu, Wenqing Shui, Jianjun Cheng, Suwen Zhao, Ling Shen, Jun Ma, Ronald J. Quinn, Raymond C. Stevens, Guisheng Zhong, Zhi-Jie Liu. Identification of natural products as novel ligands for the human 5-HT_2C receptor. Biophysics Reports, 2018, 4(1): 50-61. doi: 10.1007/s41048-018-0047-1

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Identification of natural products as novel ligands for the human 5-HT_2C receptor

doi: 10.1007/s41048-018-0047-1

1 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
2 Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China
3 iHuman Institute, ShanghaiTech University, Shanghai 201210, China
4 University of Chinese Academy of Sciences, Beijing 100049, China
5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
6 College of Pharmacy, Nankai University, Tianjin 300071, China
7 High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biotechnology and Medicine, Tianjin 300457, China
8 Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia

Funds: This work was funded by the National Nature Science Foundation of China (31330019),the Shanghai Municipal Government,ShanghaiTech University and the Institute of Molecular and Clinical Medicine,Kunming Medical University.

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Corresponding author: Guisheng Zhong,zhongsh@shanghaitech.edu.cn;Zhi-Jie Liu,liuzhj@shanghaitech.edu.cn
Received Date: 28 March 2017
Rev Recd Date: 15 May 2017
Publish Date: 28 February 2018

Abstract

Abstract

G protein-coupled receptors (GPCRs) constitute the largest human protein family with over 800 members, which are implicated in many important medical conditions. Serotonin receptors belong to the aminergic GPCR subfamily and play important roles in physiological and psychological activities. Structural biology studies have revealed the structures of many GPCRs in atomic details and provide the basis for the identification and investigation of the potential ligands, which interact with and modulate the receptors. Here, an integrative approach combining a focused target-specific natural compound library, a thermalshift-based screening method, affinity mass spectrometry, molecular docking, and in vitro as well as in vivo functional assay, was applied to identify (-)-crebanine and several other aporphine alkaloids as initial hits for a human serotonin receptor subtype, the 5-HT_2C receptor. Further studies illuminated key features of their binding affinity, downstream signaling and tissue reaction, providing a molecular explanation for the interaction between (-)-crebanine and human 5-HT_2C receptor.
- GPCR,
- 5-HT_2C receptor,
- Natural product,
- Alkaloids

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参考文献

Ahn K (2016) Worldwide trend of botanical drug and strategies for developing global drugs. BMB Rep 50(3):111-116

Alexandrov AI, Mileni M, Chien EY, Hanson MA, Stevens RC (2008) Microscale fluorescent thermal stability assay for membrane proteins. Structure 16:351-359

All natural (2007) Nat Chem Biol 3:351

Bartley JP, Baker LT, Carvalho CF (1994) Alkaloids of Stephania bancroftii. Phytochemistry 36:1327-1331

Besnard J, Ruda GF, Setola V, Abecassis K, Rodriguiz RM, Huang XP, Norval S, Sassano MF, Shin AI, Webster LA, Simeons FR, Stojanovski L, Prat A, Seidah NG, Constam DB, Bickerton GR, Read KD, Wetsel WC, Gilbert IH, Roth BL, Hopkins AL (2012) Automated design of ligands to polypharmacological profiles. Nature 492:215-220

Chen X, Qin S, Chen S, Li J, Li L, Wang Z, Wang Q, Lin J, Yang C, Shui W (2015) A ligand-observed mass spectrometry approach integrated into the fragment based lead discovery pipeline. Sci Rep 5:8361

Cheng J, McCorvy JD, Giguere PM, Zhu H, Kenakin T, Roth BL, Kozikowski AP (2016) Design and discovery of functionally selective serotonin 2C (5-HT2C) receptor agonists. J Med Chem 59:9866-9880

Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV (1997) Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 337:581-588

Englisch S, Jung HS, Lewien A, Becker A, Nowak U, Braun H, Thiem J, Eisenacher S, Meyer-Lindenberg A, Zink M (2016) Agomelatine for the treatment of major depressive episodes in schizophrenia-spectrum disorders:an open-prospective proof-of-concept study. J Clin Psychopharmacol 36(6):597-607

Halford JC, Harrold JA (2012) 5-HT(2C) receptor agonists and the control of appetite. Handb Exp Pharmacol. https://doi.org/10.1007/978-3-642-24716-3_16

Hannon J, Hoyer D (2008) Molecular biology of 5-HT receptors. Behav Brain Res 195:198-213

Hanson MA, Brooun A, Baker KA, Jaakola VP, Roth C, Chien EY, Alexandrov A, Velasquez J, Davis L, Griffith M, Moy K, GanserPornillos BK, Hua Y, Kuhn P, Ellis S, Yeager M, Stevens RC (2007) Profiling of membrane protein variants in a baculovirus system by coupling cell-surface detection with smallscale parallel expression. Protein Expr Purif 56:85-92

Huang XP, Karpiak J, Kroeze WK, Zhu H, Chen X, Moy SS, Saddoris KA, Nikolova VD, Farrell MS, Wang S, Mangano TJ, Deshpande DA, Jiang A, Penn RB, Jin J, Koller BH, Kenakin T, Shoichet BK, Roth BL (2015) Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527:477-483

Isberg V, Mordalski S, Munk C, Rataj K, Harpsøe K, Hauser AS, Vroling B, Bojarski AJ, Vriend G, Gloriam DE (2016) GPCRdb:an information system for G protein-coupled receptors. Nucleic Acids Res 44:D356-D364

Jacobson KA (2015) New paradigms in GPCR drug discovery. Biochem Pharmacol 98:541-555

Jang HJ, Cho KH, Park SW, Kim MJ, Yoon SH, Rhie DJ (2012) Layerspecific serotonergic facilitation of IPSC in layer 2/3 pyramidal neurons of the visual cortex. J Neurophysiol 107:407-416

Kroeze WK, Sassano MF, Huang XP, Lansu K, McCorvy JD, Gigue`re PM, Sciaky N, Roth BL (2015) PRESTO-Tango as an opensource resource for interrogation of the druggable human GPCRome. Nat Struct Mol Biol 22:362-369

Lv X, Liu J, Shi Q, Tan Q, Wu D, Skinner JJ, Walker AL, Zhao L, Gu X, Chen N, Xue L, Si P, Zhang L, Wang Z, Katritch V, Liu ZJ, Stevens RC (2016) In vitro expression and analysis of the 826 human G protein-coupled receptors. Protein Cell 7:325-337

McCorvy JD, Roth BL (2015) Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther 150:129-142

Narayanaswami V, Dwoskin LP (2016) Obesity:current and potential pharmacotherapeutics and targets. Pharmacol Ther 170:116-147

Newman DJ, Cragg GM (2016) Natural Products as sources of new drugs from 1981 to 2014. J Nat Prod 79:629-661

Nichols DE, Frescas S, Marona-Lewicka D, Kurrasch-Orbaugh DM (2002) Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N, N-diethyllysergamide (LSD). J Med Chem 45:4344-4349

Qin S, Ren Y, Fu X, Shen J, Chen X, Wang Q, Bi X, Liu W, Li L, Liang G, Yang C, Shui W (2015) Multiple ligand detection and affinity measurement by ultrafiltration and mass spectrometry analysis applied to fragment mixture screening. Anal Chim Acta 886:98-106

Rask-Andersen M, Masuram S, Schioth HB (2014) The druggable genome:evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication. Annu Rev Pharmacol Toxicol 54:9-26

Santos R, Ursu O, Gaulton A, Bento AP, Donadi RS, Bologa CG, Karlsson A, Al-Lazikani B, Hersey A, Oprea TI, Overington JP (2017) A comprehensive map of molecular drug targets. Nat Rev Drug Discov 16:19-34

Shang JH, Cai XH, Feng T, Zhao YL, Wang JK, Zhang LY, Yan M, Luo XD (2010) Pharmacological evaluation of Alstonia scholaris:anti-inflammatory and analgesic effects. J Ethnopharmacol 129:174-181

Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM (2013) Molecular signatures of G-protein-coupled receptors. Nature 494:185-194

Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC (2013) Structural features for functional selectivity at serotonin receptors. Science 340:615-619

Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, Lansu K, Schools ZL, Che T, Nichols DE, Shoichet BK, Dror RO, Roth BL (2017) Crystal structure of an LSD-bound human serotonin receptor. Cell 168(377-389):e312

Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang XP, Vardy E, McCorvy JD, Gao X, Zhou XE, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, Xu HE (2013) Structural basis for molecular recognition at serotonin receptors. Science 340:610-614

Xu X, Wang ZT, Yu GD, Ruan BF, Li J (2002) Alkaloids from Rhizoma corydalis. Journal of China Pharm Univ 33:483-486

Yin X, Bai R, Guo Q, Su G, Wang J, Yang X, Li L, Tu P, Chai X (2016) Hendersine A, a novel isoquinoline alkaloid from Corydalis hendersonii. Tetrahedron Lett 57:4858-4862

Yuan S, Peng Q, Palczewski K, Vogel H, Filipek S (2016) Mechanistic studies on the stereoselectivity of the serotonin 5-HT1A receptor. Angew Chem Int Ed Engl 55:8661-8665

Zeeb FD, Higgins GA, Fletcher PJ (2015) The serotonin 2C receptor agonist lorcaserin attenuates intracranial self-stimulation and blocks the reward-enhancing effects of nicotine. ACS Chem Neurosci 6:1231-1240

Zhong M, Jiang YB, Chen YL, Yan Q, Liu JX, Di DL (2015) Asymmetric total synthesis of (S)-isocorydine. Tetrahedron 26:1145-1149

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