Currently 30-50% of drug targets are G Protein-Coupled Receptors (GPCRs). However, the clinical useful drugs for targeting GPCR have been limited by the lack of subtype selectivity or efficacy, leading to undesirable side effects. To develop subtype-selective GPCR ligands with desired molecular properties, better understanding is needed of the pharmacophore elements and of the binding mechanism required for subtype selectivity. To illustrate these issues, we describe here three successful applications to understand the binding mechanism associated with subtype selectivity: 5-HT2B (5-Hydroxytryptamine, 5-HT) serotonin receptor (HT2BR), H3 histamine receptor (H3HR) and A3 adenosine receptor (A3AR). The understanding of structure-function relationships among individual types and subtypes of GPCRs gained from such computational predictions combined with experimental validation and testing is expected the development of new highly selective and effective ligands to address such diseases while minimizing side-effects.
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Endogenous ligands regulate multiple GPCR subtypes. Serotonin activates 15 serotonin (5-HT) receptors. With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all other 14 serotonin receptors are GPCRs. The 5-HT1 (1A- 1F) and 5-HT5 (5A, 5B) receptors decrease cellular level of cAMP through coupling with Gi/ Go protein, while 5HT4, 5-HT6, and 5-HT7 receptors increase cellular level of cAMP through coupling with Gs protein. 5-HT2 (2A– 2C) receptors increase cellular level of inositol triphosphate (IP3) and diacylglycerol (DAG) through coupling with Gq/ G11 protein (Nichols & Nichols, 2008 ). Various biological and neurological processes were regulated through the serotonin receptors such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Thus, the serotonin receptors are the target of a variety of pharmaceutical drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens (Nichols & Nichols, 2008).
Histamine acts via four histamine receptors (HRs); H1, H2, H3 and H4. Histamine has a critical role in immumomodulation and allergic diseases. Other biological activities include cell proliferation, differentiation, hematopoiesis, embryonic development, regeneration, wound healing, aminergic neurotransmission, secretion of pituitary hormones and regulation of gastrointestinal and circulatory functions (Jutel, Blaser, & Akdis, 2005). The H3 and H4 HRs inhibit the cellular level of cAMP through coupling with Gi/ Go protein, while the H2HR activates the cellular level of cAMP through coupling with Gs protein. The H1HR increases the cellular level of IP3 and DAG through coupling with Gq/ G11 protein.
Adenosine binds all 4 subtypes of adenosine receptors (ARs), denoted A1, A2A, A2B, and A3, which coupled to G proteins. Activation of the A1 and A3 ARs inhibit the cellular level of cAMP via Gi/ Go protein, while the A2A and A2B ARs activate the cellular level of cAMP via Gs protein (Olah & Stiles, 1995). ARs are involved in many of the body’s cytoprotective functions. Thus, ARs are important pharmacological targets in the treatment of a variety of diseases because of their key roles in controlling numerous physiological processes. For example, many therapeutic agents under development for treatment of central nervous system disorders, inflammatory diseases, asthma, kidney failure and ischemic injuries exert their effects via interactions with ARs.