Review
Pharmacology & Pharmacy
Anh T. N. Nguyen, Diep T. N. Nguyen, Huan Yee Koh, Jason Toskov, William MacLean, Andrew Xu, Daokun Zhang, Geoffrey I. Webb, Lauren T. May, Michelle L. Halls
Summary: The application of artificial intelligence in drug discovery for G protein-coupled receptors (GPCRs) is expanding rapidly. It can assist in understanding the actions of GPCRs, discovering new ligand-GPCR interactions, and predicting clinical responses. This article provides an overview of artificial intelligence concepts and its applications in different stages of GPCR drug discovery. The benefits and limitations of artificial intelligence are discussed, along with the potential for further development in assisting GPCR drug discovery.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Roberto Maggio, Irene Fasciani, Francesco Petragnano, Maria Francesca Coppolino, Marco Scarselli, Mario Rossi
Summary: Unstructured regions in functional proteins, specifically the i3 loop and C-terminus in G protein-coupled receptors (GPCRs), have been recognized as crucial elements in GPCR function and regulation. They play critical roles in allosterically regulating GPCR activation, as autoregulators in receptor coupling specificity, and in facilitating receptor stability and interactions with intracellular protein partners.
Review
Pharmacology & Pharmacy
Bui San Thai, Ling Yeong Chia, Anh T. N. Nguyen, Chengxue Qin, Rebecca H. Ritchie, Dana S. Hutchinson, Andrew Kompa, Paul J. White, Lauren T. May
Summary: Heart failure remains a significant cause of morbidity and mortality worldwide. Current treatment options have limitations, leading to many patients progressing to advanced stages. Exploration of novel therapeutics targeting G protein-coupled receptors (GPCRs) has shown promise, but efficacy and unwanted effects remain as challenges.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mingcheng Qian, Zhijie Luo, Wenwen Hou, Jingjing Sun, Xin Lu, Qianxi Zhang, Yi Wu, Caile Xue, Shuai Zhao, Xin Chen
Summary: In this study, fourteen new cholic acid derivatives were designed and synthesized, and one of them, B1, was found to be a highly potent TGR5 agonist, which can be used as a lead compound for further study.
BIOORGANIC CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Joshua W. Conner, Daniel P. Poole, Manuela Jorg, Nicholas A. Veldhuis
Summary: This review addresses the key challenges, synthesis approaches, and structure-activity relationships in recent fluorescent small molecule studies for GPCRs, and discusses the advantages of using high-resolution GPCR structures to inform conjugation strategies.
FUTURE MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Peyton High, Kendra S. Carmon
Summary: In recent years, antibody-drug conjugates (ADCs) have shown great potential as anti-cancer therapeutic agents, and some have been approved for the treatment of solid tumors and hematological malignancies. G protein-coupled receptors (GPCRs), which are known therapeutic targets in various human diseases including cancer, have emerged as a promising target for ADCs. This review discusses the past and current therapeutic targeting of GPCRs and describes the use of ADCs as a therapeutic modality. Additionally, the status of preclinical and clinical GPCR-targeted ADCs is summarized, and the potential of GPCRs as novel targets for future ADC development is addressed.
Article
Biochemical Research Methods
Tien L. Olson, Shangji Zhang, Dillon Labban, Emily Kaschner, Manuel Aceves, Srivatsan Iyer, Jose Domingo Meza-Aguilar, James D. Zook, Eugene Chun, Felicia M. Craciunescu, Wei Liu, Chang-Xin Shi, A. Keith Stewart, Debra T. Hansen, Nathalie Meurice, Petra Fromme
Summary: GRK6 is a key kinase involved in multiple myeloma, phosphorylating GPCRs to mediate cell survival, proliferation, and migration. Three GRK6 constructs were successfully purified for co-crystallization studies, with the His10 affinity tag enhancing purification yields. These methods will facilitate the development of structure-based therapeutics against multiple myeloma.
PROTEIN EXPRESSION AND PURIFICATION
(2021)
Article
Biochemistry & Molecular Biology
Damian Jacenik, Pawel Hikisz, Ellen J. Beswick, Jakub Fichna
Summary: Among the various adhesion G protein-coupled receptors, ADGRF5 stands out with its unique domains in the N-terminal tail that play a critical role in cell-cell and cell-matrix interactions, as well as cell adhesion. Although the biology of ADGRF5 is still not fully understood, accumulating evidence suggests its fundamental importance in both health and disease. Recent studies have highlighted its potential diagnostic value in osteoporosis and cancers, and ongoing research indicates its relevance to other diseases as well. This article provides a comprehensive overview of the current understanding of ADGRF5 in human disease physiology and pathophysiology, emphasizing its potential as a novel therapeutic target in various areas.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Review
Pharmacology & Pharmacy
Jia Fu, Wei Qin, Lu-Qi Cao, Zhe-Sheng Chen, Hui-Ling Cao
Summary: This review summarizes the applications and immobilization methods of receptor chromatography, which is widely used for high-throughput separation and accurate drug screening. The review focuses on screening active compounds in natural products, as well as the design and application of receptor chromatography in drug-receptor interactions.
DRUG DISCOVERY TODAY
(2023)
Review
Pharmacology & Pharmacy
Mydirah Littlepage-Saunders, Michael J. Hochstein, Doris S. Chang, Kari A. Johnson
Summary: Dopamine transmission in the striatum is regulated by various G protein-coupled receptors (GPCRs) that bind neuromodulators, including dopamine itself. These GPCRs can modulate dopamine release by acting on different components of the dopaminergic circuitry and can have distinct effects on behavior and psychoactive drug actions. This review discusses the mechanisms by which GPCRs regulate dopaminergic transmission and their relevance to the effects of psychoactive drugs on physiology and behavior.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Genetics & Heredity
Mengyan Zhang, Jiyun Zhao, Huili Dong, Wenhui Xue, Jie Xing, Ting Liu, Xiuwen Yu, Yue Gu, Baoqing Sun, Haibo Lu, Yan Zhang
Summary: Tumor heterogeneity poses challenges for cancer diagnosis and treatment. This study proposes a computational method to quantify the specificity of GPCRs DNA methylation and identifies specific GPCRs DNA methylation biomarkers. Potential drugs were discovered through predicting drug sensitivities. Specific biomarkers were validated in various cancers.
Article
Endocrinology & Metabolism
Roger D. Jones, Alan M. Jones
Summary: We propose a model that examines the effects of ligands on information transmission in G-Protein Coupled Receptor(GPCR) complexes. The model is based on statistical mechanics and information transmission theory and was validated through in vitro observations and single-cell experiments. The model predicts the role of phosphatase-catalyzed reactions in controlling signaling activity, the statistical balance between ON and OFF switches in signaling, and the discontinuous relationship between biased-signaling response and ligand concentration.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Dehua Yang, Qingtong Zhou, Viktorija Labroska, Shanshan Qin, Sanaz Darbalaei, Yiran Wu, Elita Yuliantie, Linshan Xie, Houchao Tao, Jianjun Cheng, Qing Liu, Suwen Zhao, Wenqing Shui, Yi Jiang, Ming-Wei Wang
Summary: Recent progress in understanding the structure-function relationships of G protein-coupled receptors has accelerated drug development significantly. This article aims to provide a comprehensive overview of this important field to a broader readership interested in drug discovery.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2021)
Review
Pharmacology & Pharmacy
Alastair C. Keen, Manuela Jorg, Michelle L. L. Halls
Summary: The ubiquitin-proteasome system is a major pathway for protein degradation in cells, and methods have been developed to exploit this system for targeted protein degradation. Targeted protein degraders have been useful tools in discovery research and are being developed as therapeutics. However, most targeted protein degrader technologies have been developed for cytosolic proteins, while examples for G protein-coupled receptor (GPCR) degradation are limited. This review discusses the strategies used for applying targeted protein degradation to GPCRs and explores alternative approaches used for degrading other integral membrane proteins.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Cell Biology
Haoran Jiang, Daniella Galtes, Jialu Wang, Howard A. Rockman
Summary: This review explores the signaling pathways, dynamic structures, and physiological relevance of the three most important GPCR signaling effectors in the cardiovascular system: heterotrimeric G proteins, GPCR kinases (GRKs), and 8-arrestins. It summarizes their prominent roles in GPCR pharmacology before transitioning into less well-explored areas. The application of new technologies has contributed to an increasing understanding of GPCR structure and downstream effectors.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)