Author: Grotsch, Katharina ; Zaidi, Saheem ; Liu, Yongfeng ; Makriyannis, Alexandros ; Le, Austen ; Katritch, Vsevolod ; Sadybekov, Anastasiia V ; Eremin, Dmitry ; Thomas, Joice ; Aggarwal, Shubhangi ; Picazo, Elias ; Pickett, Julie E ; Illiopoulis-Tsoutsouvas, Christos ; Fokin, Valery V ; Roth, Bryan L ; Reyes, Cesar ; Hiller, Sydney ; Smith, Evan Carlton

The advent of ultra-large libraries of drug-like compounds has significantly broadened the possibilities in structure-based virtual screening, accelerating the discovery and optimization of high-quality lead chemotypes for diverse clinical targets. Compared to traditional high-throughput screening, which is constrained to libraries of approximately one million compounds, the ultra-large virtual screening approach offers substantial advantages in both cost and time efficiency. By expanding the chemical space with compounds synthesized from easily accessible and reproducible reactions and utilizing a large, diverse set of building blocks, we can enhance both the diversity and quality of the discovered lead chemotypes. In this study, we explore new chemical spaces using reactions of sulfur(VI) fluorides to create a combinatorial library consisting of several hundred million compounds. We screened this virtual library for cannabinoid type II receptor (CB₂) antagonists using the high-resolution structure in conjunction with a rationally designed antagonist, AM10257. The top-predicted compounds were then synthesized and tested in vitro for CB₂ binding and functional antagonism, achieving an experimentally validated hit rate of 55%. Our findings demonstrate the effectiveness of reliable reactions, such as sulfur fluoride exchange, in diversifying ultra-large chemical spaces and facilitate the discovery of new lead compounds for important biological targets.

23 Sep 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Rational Remodeling of Atypical Scaffolds for the Design of Photoswitchable Cannabinoid Receptor Tools

Q1 · MEDICINE

Article

Author: Tian, Cuiping ; Hu, Tao ; Stevens, Raymond C. ; Makriyannis, Alexandros ; Zhong, Guisheng ; Tao, Houchao ; Xu, Yueming ; Hua, Tian ; Zhao, Suwen ; Liu, Zhi-Jie ; Xie, Linshan ; Zheng, Guoxun ; Zhao, Fei ; Xue, Dongxiang ; Zhou, Fang ; Zhao, Simeng ; Li, Fei

Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority. Herein, we investigate the rational remodeling of atypical scaffolds for azobenzene introduction, as exemplified in the development of photoswitchable ligands for the cannabinoid receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding the binding pocket, we conclude that among the three representative atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is the most appropriate for azobenzene remodeling. The optimizing spacer length and attachment position revealed AzoLig 9 with excellent thermal bistability, decent photopharmacological switchability between its two configurations, and high subtype selectivity. This structure-guided approach gave new impetus in the extension of new chemical spaces for tool customization for increasingly diversified photo-pharmacological studies and beyond.

01 Jan 2019·CellQ1 · BIOLOGY

Crystal Structure of the Human Cannabinoid Receptor CB2

Q1 · BIOLOGY

Article

Author: Cinar, Resat ; Liu, Zhi-Jie ; Wu, Meng ; Bohn, Laura M ; Qu, Lu ; Ho, Jo-Hao ; Kunos, George ; Hua, Tian ; Wang, Jingjing ; Vemuri, Kiran ; Han, Gye Won ; Wu, Yiran ; Coffey, Nathan J ; Benchama, Othman ; Zhao, Suwen ; Zvonok, Nikolai ; Popov, Petr ; Wu, Lijie ; Iyer, Malliga R ; Stevens, Raymond C ; Li, Xiaoting ; Makriyannis, Alexandros ; Locke, K'ara ; Katritch, Vsevolod

The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.

100 Deals associated with AM-10257

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis	Preclinical	China	CAS Center for Excellence in Molecular Cell Science	01 Jan 2019
Fibrosis	Preclinical	China	Shanghaitech University	01 Jan 2019
Fibrosis	Preclinical	China	University of Chinese Academy of Sciences	01 Jan 2019
Inflammation	Preclinical	China	Shanghaitech University	01 Jan 2019
Inflammation	Preclinical	China	University of Chinese Academy of Sciences	01 Jan 2019
Inflammation	Preclinical	China	CAS Center for Excellence in Molecular Cell Science	01 Jan 2019
Neurodegenerative Diseases	Preclinical	China	CAS Center for Excellence in Molecular Cell Science	01 Jan 2019
Neurodegenerative Diseases	Preclinical	China	University of Chinese Academy of Sciences	01 Jan 2019
Neurodegenerative Diseases	Preclinical	China	Shanghaitech University	01 Jan 2019

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