Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery
G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including G proteins (such as Gi/o, Gs, G12, and Gq) and β-arrestins (such as β-arrestin 1 and β-arrestin 2) to...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S104366182400519X |
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| author | Xin Qiao Xiaolong Li Mingyang Zhang Ning Liu Yanmei Wu Shaoyong Lu Ting Chen |
| author_facet | Xin Qiao Xiaolong Li Mingyang Zhang Ning Liu Yanmei Wu Shaoyong Lu Ting Chen |
| author_sort | Xin Qiao |
| collection | DOAJ |
| description | G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including G proteins (such as Gi/o, Gs, G12, and Gq) and β-arrestins (such as β-arrestin 1 and β-arrestin 2) to mediate diverse cellular and physiological responses. Biased signaling allows for the specific activation of certain pathways from the full range of receptors’ signaling capabilities. Targeting more variable allosteric sites, which are spatially different from the highly conserved orthosteric sites, represents a novel approach in biased GPCR drug discovery, leading to innovative strategies for targeting GPCRs. Notably, the emergence of cryptic allosteric sites on GPCRs has expanded the repertoire of available drug targets and improved receptor subtype selectivity. Here, we conduct a summary of recent progress in the structural determination of cryptic allosteric sites on GPCRs and elucidate the biased signaling mechanisms induced by allosteric modulators. Additionally, we discuss means to identify cryptic allosteric sites and design biased allosteric modulators based on cryptic allosteric sites through structure-based drug design, which is an advanced pharmacotherapeutic approach for treating GPCR-associated diseases. |
| format | Article |
| id | doaj-art-aedeee6912564be6b3728ee9d963c7a2 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-aedeee6912564be6b3728ee9d963c7a22025-02-08T04:59:37ZengElsevierPharmacological Research1096-11862025-02-01212107574Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discoveryXin Qiao0Xiaolong Li1Mingyang Zhang2Ning Liu3Yanmei Wu4Shaoyong Lu5Ting Chen6Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan 750004, ChinaDepartment of Orthopedics, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, ChinaMedicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaKey Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan 750004, ChinaDepartment of General Surgery, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; Corresponding authors.Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; Corresponding author at: Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.Department of Cardiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China; Corresponding authors.G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including G proteins (such as Gi/o, Gs, G12, and Gq) and β-arrestins (such as β-arrestin 1 and β-arrestin 2) to mediate diverse cellular and physiological responses. Biased signaling allows for the specific activation of certain pathways from the full range of receptors’ signaling capabilities. Targeting more variable allosteric sites, which are spatially different from the highly conserved orthosteric sites, represents a novel approach in biased GPCR drug discovery, leading to innovative strategies for targeting GPCRs. Notably, the emergence of cryptic allosteric sites on GPCRs has expanded the repertoire of available drug targets and improved receptor subtype selectivity. Here, we conduct a summary of recent progress in the structural determination of cryptic allosteric sites on GPCRs and elucidate the biased signaling mechanisms induced by allosteric modulators. Additionally, we discuss means to identify cryptic allosteric sites and design biased allosteric modulators based on cryptic allosteric sites through structure-based drug design, which is an advanced pharmacotherapeutic approach for treating GPCR-associated diseases.http://www.sciencedirect.com/science/article/pii/S104366182400519XG protein-coupled receptorsBiased signalingCryptic allosteric sitesAllosteric modulatorsDrug design |
| spellingShingle | Xin Qiao Xiaolong Li Mingyang Zhang Ning Liu Yanmei Wu Shaoyong Lu Ting Chen Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery Pharmacological Research G protein-coupled receptors Biased signaling Cryptic allosteric sites Allosteric modulators Drug design |
| title | Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery |
| title_full | Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery |
| title_fullStr | Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery |
| title_full_unstemmed | Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery |
| title_short | Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery |
| title_sort | targeting cryptic allosteric sites of g protein coupled receptors as a novel strategy for biased drug discovery |
| topic | G protein-coupled receptors Biased signaling Cryptic allosteric sites Allosteric modulators Drug design |
| url | http://www.sciencedirect.com/science/article/pii/S104366182400519X |
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