Cannabinoid CB2 Receptor Structure and Allosteric Modulators
大麻素 CB2 受体结构和变构调节剂
基本信息
- 批准号:10612431
- 负责人:
- 金额:$ 63.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-15 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAffinityAgonistAlgorithmsAllosteric SiteAntibodiesAutoimmune DiseasesBindingBinding SitesBiological AssayBiologyBrain regionCNR1 geneCNR2 geneCannabinoidsChemicalsChronicComplexCryoelectron MicroscopyCyclic AMPDatabasesDetergentsDevelopmentDiseaseDockingDrug TargetingExhibitsFamilyG-Protein-Coupled ReceptorsGTP-Binding ProteinsGenomicsGoalsHeterogeneityHumanHydrophobicityImmuneIn VitroInflammatoryJointsLegal patentLibrariesLigand BindingLigandsMachine LearningMalignant NeoplasmsMeasuresMembrane ProteinsMethodsModelingMolecularMolecular ConformationMolecular ProfilingMutationNeurologicOsteoporosisOutcomePainPharmaceutical ChemistryPharmacologyPilot ProjectsPropertyPublicationsPublishingReportingResearchResistance developmentRoentgen RaysRoleSignal TransductionSiteSite-Directed MutagenesisStructureSynthesis ChemistrySystemTechniquesTechnologyTherapeuticTissuesValidationWorkX-Ray Crystallographyaddictionalternative treatmentantagonistcannabinoid receptorcheminformaticscomputational chemistrydeep learningdesigndrug developmentdrug discoveryendogenous cannabinoid systemimprovedin silicoin vivoinnovationinsightinterestlearning classifiermachine learning classifierneuroinflammationnovelpharmacophorepositive allosteric modulatorpressurepreventprospectiveprototypereceptorscreeningsmall moleculesmall molecule librariesspatiotemporalstructural biologysynthetic cannabinoidtargeted treatmenttherapeutic targetthree dimensional structuretoolvirtual
项目摘要
Cannabinoid receptor subtype 2 (CB2) is a class-A family G protein-coupled receptor (GPCR), located primarily
in immune-associated tissues but also in specific regions of the brain, and implicated in several inflammatory
diseases and addiction. Drugs targeting CB2 are attractive treatment alternatives for chronic neurological pain
and neuroinflammatory autoimmune diseases since they avoid deleterious psychotropic effects that are
associated with CB1. While drug development efforts have been primarily focused on small molecules targeting
the orthosteric site, limitations of poor selectivity, lack of efficacy, and development of resistance have hampered
such effort. At present, there is great interests in identifying GPCR allosteric modulators that either enhance
(positive allosteric modulators, or PAMs) or inhibit (negative allosteric modulators, or NAMs) agonist-induced
receptor activity. PAMs/NAMs often exhibit improved subtype selectivity and spatiotemporal sensitivity, as well as
potential biased signaling properties compared to orthosteric ligands. We have recently reported a 3.2 Å cryo-EM
structure of the agonist-bound human CB2-Gi complex. Based on such progress, the overall goals of this proposal
are to obtain a structural understanding of CB2 allosteric modulation and use our integrated computational and
experimental medicinal chemistry/biology approaches to design and synthesize novel allosteric modulators for the
development of CB2-specific small-molecules with potential to treat CB2-associated maladies. Thus, we first propose
to elucidate the structural basis for the action of CB2 allosteric modulators by cryo-EM and X-ray crystallography
approaches. To achieve the goal, we will advance our established methods for structural studies on CB2 to obtain
structure of CB2 with known PAMs or NAMs. Subsequently, we plan to perform in silico design of novel CB2 allosteric
modulators by our established molecular fingerprint machine-learning (ML) computing algorithms and receptor
docking approaches, on basis of our reported chemogenomics cannabinoid molecular information database (CBID)
and 3D CB2-Gi cryo-EM structure; a virtual allosteric modulator library will be constructed using our fragment-based
design (FBD) method and our established ML-classifiers and features-ranking will be applied for selection of virtual
hits. Results will be correlated with CB2 structure-based modulator design via adapting the structural information
obtained from our recent CB2-Gi cryo-EM structure and our novel molecular complex characterizing system (MCCS)
algorithm. Finally, we will carry out medicinal chemistry synthesis of CB2 PAM and NAM ligands and validate them
by radiometric binding and cellular functional assays. With the proof-of-evidence of our recent discovery of a putative
CB2 NAM, successful completion of these Aims will provide unprecedented structural information on CB2 allosteric
pockets, identify promising new CB2 allosteric modulators, and help to elucidate CB2 signaling and pharmacology.
大麻素受体亚型2 (Cannabinoid receptor subtype 2, CB2)是一种a类家族G蛋白偶联受体(GPCR),主要位于
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Differential performance of RoseTTAFold in antibody modeling.
RoseTTAFold 在抗体建模中的差异化性能。
- DOI:10.1093/bib/bbac152
- 发表时间:2022
- 期刊:
- 影响因子:9.5
- 作者:Liang,Tianjian;Jiang,Chen;Yuan,Jiayi;Othman,Yasmin;Xie,Xiang-Qun;Feng,Zhiwei
- 通讯作者:Feng,Zhiwei
Artificial Intelligent Deep Learning Molecular Generative Modeling of Scaffold-Focused and Cannabinoid CB2 Target-Specific Small-Molecule Sublibraries.
- DOI:10.3390/cells11050915
- 发表时间:2022-03-07
- 期刊:
- 影响因子:6
- 作者:Bian Y;Xie XQ
- 通讯作者:Xie XQ
How Do Modulators Affect the Orthosteric and Allosteric Binding Pockets?
- DOI:10.1021/acschemneuro.1c00749
- 发表时间:2022-04-06
- 期刊:
- 影响因子:5
- 作者:Chen, Chih-Jung;Jiang, Chen;Yuan, Jiayi;Chen, Maozi;Cuyler, Jacob;Xie, Xiang-Qun;Feng, Zhiwei
- 通讯作者:Feng, Zhiwei
Discovery of a pyrano[2,3-b]pyridine derivative YX-2102 as a cannabinoid receptor 2 agonist for alleviating lung fibrosis.
发现pyrano [2,3-B]吡啶衍生物YX-2102作为大麻素受体2激动剂,用于减轻肺纤维化。
- DOI:10.1186/s12967-022-03773-1
- 发表时间:2022-12-06
- 期刊:
- 影响因子:7.4
- 作者:Liu, Tao;Gu, Jing;Yuan, Yi;Yang, Qunfang;Zheng, Peng-Fei;Shan, Changyu;Wang, Fangqin;Li, Hongwei;Xie, Xiang-Qun;Chen, Xiao-Hong;Ouyang, Qin
- 通讯作者:Ouyang, Qin
Integrated Multi-Class Classification and Prediction of GPCR Allosteric Modulators by Machine Learning Intelligence.
- DOI:10.3390/biom11060870
- 发表时间:2021-06-11
- 期刊:
- 影响因子:5.5
- 作者:Hou T;Bian Y;McGuire T;Xie XQ
- 通讯作者:Xie XQ
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{{ truncateString('Xiang-Qun Xie', 18)}}的其他基金
SmartAD for Intelligent Alzheimer’s Disease(AD) Personalized Combination Therapy
SmartAD 智能阿尔茨海默病 (AD) 个性化联合治疗
- 批准号:
10701069 - 财政年份:2022
- 资助金额:
$ 63.31万 - 项目类别:
SmartAD for Intelligent Alzheimer’s Disease(AD) Personalized Combination Therapy
SmartAD 智能阿尔茨海默病 (AD) 个性化联合治疗
- 批准号:
10670481 - 财政年份:2022
- 资助金额:
$ 63.31万 - 项目类别:
Cannabinoid CB2 Receptor Structure and Allosteric Modulators
大麻素 CB2 受体结构和变构调节剂
- 批准号:
10297210 - 财政年份:2021
- 资助金额:
$ 63.31万 - 项目类别:
Cannabinoid CB2 Receptor Structure and Allosteric Modulators
大麻素 CB2 受体结构和变构调节剂
- 批准号:
10448397 - 财政年份:2021
- 资助金额:
$ 63.31万 - 项目类别:
Screen and Design p18 Chemical Probes for Hematopoietic Stem Cell Self-Renewal
用于造血干细胞自我更新的 p18 化学探针的筛选和设计
- 批准号:
8174548 - 财政年份:2011
- 资助金额:
$ 63.31万 - 项目类别:
CHEMINFORMATICS DATA-MINING FOR MOLECULAR FINGERPRINT CALCULATION
用于分子指纹计算的化学信息学数据挖掘
- 批准号:
8364201 - 财政年份:2011
- 资助金额:
$ 63.31万 - 项目类别:
Screen and Design p18 Chemical Probes for Hematopoietic Stem Cell Self-Renewal
用于造血干细胞自我更新的 p18 化学探针的筛选和设计
- 批准号:
8284383 - 财政年份:2011
- 资助金额:
$ 63.31万 - 项目类别:
CHEMINFORMATICS DATA-MINING FOR MOLECULAR FINGERPRINT CALCULATION
用于分子指纹计算的化学信息学数据挖掘
- 批准号:
8171779 - 财政年份:2010
- 资助金额:
$ 63.31万 - 项目类别:
Structure/Function of the CB2 Receptor Binding and G-protein Recognition Pockets
CB2 受体结合和 G 蛋白识别袋的结构/功能
- 批准号:
8248180 - 财政年份:2010
- 资助金额:
$ 63.31万 - 项目类别:
Structure/Function of the CB2 Receptor Binding and G-protein Recognition Pockets
CB2 受体结合和 G 蛋白识别袋的结构/功能
- 批准号:
8445348 - 财政年份:2010
- 资助金额:
$ 63.31万 - 项目类别:
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