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Background: Selectively targeting dopamine receptors (DRs) has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases involving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like). Fifteen structurally diverse ligands were docked. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for selective binding to DR subtypes. Results: Residues of the aromatic microdomain were shown to be responsible for the majority of ligand interactions established to all DRs. Hydrophobic contacts involved a huge network of conserved and non-conserved residues between three transmembrane domains (TMs), TM2-TM3-TM7. Hydrogen bonds were mostly mediated by the serine microdomain. TM1 and TM2 residues were main contributors for the coupling of large ligands. Some amino acid groups form electrostatic interactions of particular importance for D1R-like selective ligands binding. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, which will support mutagenesis studies to improve the design of subtype-specific ligands. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases affect over 30 million people worldwide with an ascending trend. Most individuals suffering from these irreversible brain damages belong to the elderly population, with onset between 50 and 60 years. Although the pathophysiology of such diseases is partially known, it remains unclear upon which point a disease turns degenerative. Moreover, current therapeutics can treat some of the symptoms but often have severe side effects and become less effective in long-term treatment. For many neurodegenerative diseases, the involvement of G proteincoupled receptors (GPCRs), which are key players of neuronal transmission and plasticity, has become clearer and holds great promise in elucidating their biological mechanism. With this review, we introduce and summarize class A and class C GPCRs, known to form heterodimers or oligomers to increase their signalling repertoire. Additionally, the examples discussed here were shown to display relevant alterations in brain signalling and had already been associated with the pathophysiology of certain neurodegenerative diseases. Lastly, we classified the heterodimers into two categories of crosstalk, positive or negative, for which there is known evidence., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The main protease of SARS-CoV-2 (M pro ), the causative agent of COVID-19, constitutes a significant drug target. A new fluorogenic substrate was kinetically compared to an internally quenched fluorescent peptide and shown to be ideally suitable for high throughput screening with recombinantly expressed M pro . Two classes of protease inhibitors, azanitriles and pyridyl esters, were identified, optimized and subjected to in-depth biochemical characterization. Tailored peptides equipped with the unique azanitrile warhead exhibited concomitant inhibition of M pro and cathepsin L, a protease relevant for viral cell entry. Pyridyl indole esters were analyzed by a positional scanning. Our focused approach towards M pro inhibitors proved to be superior to virtual screening. With two irreversible inhibitors, azanitrile 8 (k inac /K i =37 500 m -1  s -1 , K i =24.0 nm) and pyridyl ester 17 (k inac /K i =29 100 m -1  s -1 , K i =10.0 nm), promising drug candidates for further development have been discovered., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The adenosine receptor (AR) subtypes A 2A and A 2B are rhodopsin-like G s protein-coupled receptors whose expression is highly regulated under pathological, e.g. hypoxic, ischemic and inflammatory conditions. Both receptors play important roles in inflammatory and neurodegenerative diseases, are blocked by caffeine, and have now become major drug targets in immuno-oncology. By Förster resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), bimolecular fluorescence complementation (BiFC) and proximity ligation assays (PLA) we demonstrated A 2A -A 2B AR heteromeric complex formation. Moreover we observed a dramatically altered pharmacology of the A 2A AR when co-expressed with the A 2B AR (A 2B ≥ A 2A ) in recombinant as well as in native cells. In the presence of A 2B ARs, A 2A -selective ligands lost high affinity binding to A 2A ARs and displayed strongly reduced potency in cAMP accumulation and dynamic mass redistribution (DMR) assays. These results have major implications for the use of A 2A AR ligands as drugs as they will fail to modulate the receptor in an A 2A -A 2B heteromer context. Accordingly, A 2A -A 2B AR heteromers represent novel pharmacological targets., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing or financial interest.