The Retinoid and Non-Retinoid Ligands of the Rod Visual G Protein-Coupled Receptor

Abstract

G protein-coupled receptors (GPCRs) play a predominant role in the drug discovery effort. These cell surface receptors are activated by a variety of specific ligands that bind to the orthosteric binding pocket located in the extracellular part of the receptor. In addition, the potential binding sites located on the surface of the receptor enable their allosteric modulation with critical consequences for their function and pharmacology. For decades, drug discovery focused on targeting the GPCR orthosteric binding sites. However, finding that GPCRs can be modulated allosterically opened a new venue for developing novel pharmacological modulators with higher specificity. Alternatively, focus on discovering of non-retinoid small molecules beneficial in retinopathies associated with mutations in rhodopsin is currently a fast-growing pharmacological field. In this review, we summarize the accumulated knowledge on retinoid ligands and non-retinoid modulators of the light-sensing GPCR, rhodopsin and their potential in combating the specific vision-related pathologies. Also, recent findings reporting the potential of biologically active compounds derived from natural products as potent rod opsin modulators with beneficial effects against degenerative diseases related to this receptor are highlighted here.

Class A G Protein-Coupled Receptor Antagonist Famotidine as a Therapeutic Alternative against SARS-CoV2: An In Silico Analysis

“…Thus, we performed the molecular docking analysis to determine the binding free energies and the binding pattern of such compounds to the SARS-CoV2 PLpro, and we compared the results to those obtained for famotidine. Firstly, using the crystal structure of PLpro (PDB ID: 6WUC) and Castp 3.0 software, we performed topological analysis of the substrate-binding pocket of the SARS-CoV2 PLpro [ 28 ]. This pocket exhibits a solvent-accessible area of ~60 Å and it involves the following residues: Trp106, Asn109, Cys111, Tyr112, Leu162, Gly163, Arg166, Met208, Ser245, Ala246, Tyr264, Gly271, His272, Tyr273, Thr301, and Asp302.…”

“…The obtained PDB files for each protein were further submitted to restrain the molecular mechanics refinement. All molecular dynamic simulations described in this study were performed with NAMD 2.12 [ 22 ] and VegaZZ 3.1.0.21 software [ 24 , 27 ] as described in Ortega et al [ 23 , 28 ]. For each protein, the substrate-binding site located in the catalytic site was identified by using the Achilles Blind Docking server [ 29 ] with a respective ligand.…”

Shedding light on dark adaptation

“…Abbreviations of enzymes involved in retinoid synthesis: RDH8, retinal dehydrogenase 8; RDH12, retinal dehydrogenase 12; LRAT, lecithin retinol acyltransferase; RPE65, retinyl pigment epithelium-specific protein 65; RDH5, retinal dehydrogenase 5. Adapted from Ortega and Jastrzebska (2019) Int. J. Mol.…”

Retinoid analogs and polyphenols as potential therapeutics for age-related macular degeneration

“…Additionally, beneficial effects of flavonoids are related to their direct modulatory interaction with the visual receptor, rhodopsin in photoreceptor cells. 95,97,98 Collectively, all these positive effects of flavonoids can inhibit the development or progression of AMD ( Table 2). The mechanisms of action of numerous flavonoids have been evaluated in the AMD-related in vitro and in vivo models relevant to vision and this ocular pathology.…”

“…82–84,86,88–90 Flavonoids exhibit health benefits in multiple eye pathologies, including cataract, glaucoma, diabetic retinopathy, retinitis pigmentosa, and AMD. 91–95 The positive effects of flavonoids in preventing or slowing down AMD are likely related to their role in decreasing health risk factors, such as obesity, hypercholesterolemia, and hypertension. 96 Lifestyle associated with unhealthy diet and smoking, as well as other environmental factors, including exposure to bright light, potentiates ROS production.…”