Identification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy

The endocannabinoid system plays an essential role in the regulation of analgesia and human immunity, and Cannabinoid Receptor 2 (CB2) has been proved to be an ideal target for the treatment of liver diseases and some cancers. In this study, we identified CB2 antagonists using a three-step “deep lea...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Mukuo Wang, Shujing Hou, Ye Liu, Dongmei Li, Jianping Lin
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	CB2 receptor antagonist deep learning pharmacophore molecular docking multi-step virtual screening Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/5d2110cbb9644b1e972d0bfd4cd9f7ab
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5d2110cbb9644b1e972d0bfd4cd9f7ab
record_format	dspace
spelling	oai:doaj.org-article:5d2110cbb9644b1e972d0bfd4cd9f7ab2021-11-11T18:38:13ZIdentification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy10.3390/molecules262166791420-3049https://doaj.org/article/5d2110cbb9644b1e972d0bfd4cd9f7ab2021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6679https://doaj.org/toc/1420-3049The endocannabinoid system plays an essential role in the regulation of analgesia and human immunity, and Cannabinoid Receptor 2 (CB2) has been proved to be an ideal target for the treatment of liver diseases and some cancers. In this study, we identified CB2 antagonists using a three-step “deep learning–pharmacophore–molecular docking” virtual screening approach. From the ChemDiv database (1,178,506 compounds), 15 hits were selected and tested by radioligand binding assays and cAMP functional assays. A total of 7 out of the 15 hits were found to exhibit binding affinities in the radioligand binding assays against CB2 receptor, with a pK<sub>i</sub> of 5.15-6.66, among which five compounds showed antagonistic activities with pIC<sub>50</sub> of 5.25–6.93 in the cAMP functional assays. Among these hits, Compound 8 with the 4H-pyrido[1,2-a]pyrimidin-4-one scaffold showed the best binding affinity and antagonistic activity with a pK<sub>i</sub> of 6.66 and pIC<sub>50</sub> of 6.93, respectively. The new scaffold could serve as a lead for further development of CB2 drugs. Additionally, we hope that the model in this study could be further utilized to identify more novel CB2 receptor antagonists, and the developed approach could also be used to design potent ligands for other therapeutic targets.Mukuo WangShujing HouYe LiuDongmei LiJianping LinMDPI AGarticleCB2 receptor antagonistdeep learningpharmacophoremolecular dockingmulti-step virtual screeningOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6679, p 6679 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CB2 receptor antagonist deep learning pharmacophore molecular docking multi-step virtual screening Organic chemistry QD241-441
spellingShingle	CB2 receptor antagonist deep learning pharmacophore molecular docking multi-step virtual screening Organic chemistry QD241-441 Mukuo Wang Shujing Hou Ye Liu Dongmei Li Jianping Lin Identification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy
description	The endocannabinoid system plays an essential role in the regulation of analgesia and human immunity, and Cannabinoid Receptor 2 (CB2) has been proved to be an ideal target for the treatment of liver diseases and some cancers. In this study, we identified CB2 antagonists using a three-step “deep learning–pharmacophore–molecular docking” virtual screening approach. From the ChemDiv database (1,178,506 compounds), 15 hits were selected and tested by radioligand binding assays and cAMP functional assays. A total of 7 out of the 15 hits were found to exhibit binding affinities in the radioligand binding assays against CB2 receptor, with a pK<sub>i</sub> of 5.15-6.66, among which five compounds showed antagonistic activities with pIC<sub>50</sub> of 5.25–6.93 in the cAMP functional assays. Among these hits, Compound 8 with the 4H-pyrido[1,2-a]pyrimidin-4-one scaffold showed the best binding affinity and antagonistic activity with a pK<sub>i</sub> of 6.66 and pIC<sub>50</sub> of 6.93, respectively. The new scaffold could serve as a lead for further development of CB2 drugs. Additionally, we hope that the model in this study could be further utilized to identify more novel CB2 receptor antagonists, and the developed approach could also be used to design potent ligands for other therapeutic targets.
format	article
author	Mukuo Wang Shujing Hou Ye Liu Dongmei Li Jianping Lin
author_facet	Mukuo Wang Shujing Hou Ye Liu Dongmei Li Jianping Lin
author_sort	Mukuo Wang
title	Identification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy
title_short	Identification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy
title_full	Identification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy
title_fullStr	Identification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy
title_full_unstemmed	Identification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy
title_sort	identification of novel antagonists targeting cannabinoid receptor 2 using a multi-step virtual screening strategy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5d2110cbb9644b1e972d0bfd4cd9f7ab
work_keys_str_mv	AT mukuowang identificationofnovelantagoniststargetingcannabinoidreceptor2usingamultistepvirtualscreeningstrategy AT shujinghou identificationofnovelantagoniststargetingcannabinoidreceptor2usingamultistepvirtualscreeningstrategy AT yeliu identificationofnovelantagoniststargetingcannabinoidreceptor2usingamultistepvirtualscreeningstrategy AT dongmeili identificationofnovelantagoniststargetingcannabinoidreceptor2usingamultistepvirtualscreeningstrategy AT jianpinglin identificationofnovelantagoniststargetingcannabinoidreceptor2usingamultistepvirtualscreeningstrategy
_version_	1718431764046675968

Identification of Novel Antagonists Targeting Cannabinoid Receptor 2 Using a Multi-Step Virtual Screening Strategy

Ejemplares similares