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Top1. Introduction
G-protein coupled receptors (GPCRs) are membrane-bound receptors that regulate a variety of biological functions. These receptors are linked to heterotrimeric guanidine nucleotide binding proteins (G proteins), which are made up of three subunits, namely Gα, Gβ and Gγ (Usman, Khawer, Rafique, Naz, & Saleem, 2020). They communicate by interacting directly with heterotrimeric G proteins on the inner side of the plasma membrane, where the GPCR behaves as an exchange factor to increase GDP release from the G protein, resulting in GTP binding and conformational activation (Oldham & Hamm, 2008). The Gα subunit binds with GTP or GDP, whereas the other Gβ and Gγ subunits create a constitutive heterodimer and bind reversibly with Gα. GPCRs are key targets for medical therapies and drug development, owing to the broad range of physiologies and pathophysiologies where GPCR targeting can have a significant impact (Campbell & Smrcka, 2018). The fact that nearly 60% of drugs in the development stage and 36% of currently marketed drugs target human GPCRs, which basically demonstrates the importance of GPCRs in drug discovery (Rask-Andersen, Almén, & Schiöth, 2011). The GPCR family has been shown to be highly linked to tumour development and metastasis. In 1986, the direct link between GPCRs and cellular transformation was established due to the discovery of the MAS oncogene (Young, Waitches, Birchmeier, Fasano, & Wigler, 1986). Identifying GPCR interacting ligands in binding modes that favour specific receptor conformations that activate selective downstream pathways is one current method to find novel GPCR therapeutics (Smith, Lefkowitz, & Rajagopal, 2018). Recent clinical trial results show that oliceridine, a novel G protein-biased MOR agonist, is efficient at alleviating postoperative pain while also reducing nausea and respiratory depression (Singla et al., 2017).
A number of GPCRs have been linked to the cyclic adenosine monophosphate (cAMP)-dependent signalling pathway. Because cAMP is involved in a number of vital activities, the associated pathways remain an attractive therapeutic target. Moreover, cAMP is implicated in the processes of proliferation, migration, apoptosis, and gene expression (Chen, Zhang, LaPorte, & Ray, 2000; Schillace & Carr, 2006). Protein kinase A (PKA) is termed “cAMP-dependent protein kinase.” PKA is a basic serine/threonine kinase that is found in all systems and tissues throughout the body and has been linked to the development and progression of several diseases (Liu, Ke, Zhang, Zhang, & Chen, 2020). cAMP-dependent protein kinase (PKA) was discovered as the first protein kinase (Walsh, Perkins, & Krebs, 1968), sequenced first (Shoji, Ericsson, Walsh, Fischer, & Titani, 1983), cloned first (Uhler et al., 1986), and also the first protein kinase for whose crystal structure was solved (Knighton et al., 1991). It serves as a prototype for the entire protein kinase superfamily, which accounts for about 2% of the human genome. cAMP is an ancient stress response signal that, for example, is a universal indicator of glucose deprivation (Taylor, Buechler, & Yonemoto, 1990). Several studies have been conducted to investigate the function, regulation, and pathogenic involvement of this signalling system. Manipulation of this signalling system has been investigated for the treatment of a variety of diseases, including cardiovascular disease, Alzheimer's disease, Parkinson's disease, ischemia, and diabetes (Sapio et al., 2017; Wild & Dell'Acqua, 2018). A light-activatable protein kinase inhibitor peptide (PKI) has been created to enable PKA inhibition in living cells (Yi, Wang, Vilela, Danuser, & Hahn). According to a recent study, blocking PKA by PKI can redirect GPCR signals toward cell proliferation in cancer cells (Hoy, Salinas Parra, Park, Kuhn, & Iglesias-Bartolome, 2020).