Comparative Study of Carborane- and Phenyl-Modified Adenosine Derivatives as Ligands for the A2A and A3 Adenosine Receptors Based on a Rigid in Silico Docking and Radioligand Replacement Assay

Abstract

Adenosine receptors are involved in many physiological processes and pathological conditions and are therefore attractive therapeutic targets. To identify new types of effective ligands for these receptors, a library of adenosine derivatives bearing a boron cluster or phenyl group in the same position was designed. The ligands were screened in silico to determine their calculated affinities for the A2A and A3 adenosine receptors. An virtual screening protocol based on the PatchDock web server was developed. In the first screening phase, the effects of the functional group (organic or inorganic modulator) on the adenosine ligand affinity for the receptors were determined. Then, the lead compounds were identified for each receptor in the second virtual screening phase. Two pairs of the most promising ligands, compounds 3 and 4, and two ligands with lower affinity scores (compounds 11 and 12, one with a boron cluster and one with a phenyl group) were synthesized and tested in a radioligand replacement assay for affinity to the A2A and A3 receptors. A reasonable correlation of in silico and biological assay results was observed. In addition, the effects of a phenyl group and boron cluster, which is new adenosine modifiers, on the adenosine ligand binding were compared.

New keys for old locks: carborane-containing drugs as platforms for mechanism-based therapies

“…33 Indeed, these compounds opened up new possibilities for the design of novel AdR modulators and agents affecting inflammatory mechanisms, as recent in silico studies on AdRs A 2A and A 3 have demonstrated. 35 In the wide field of human purinergic receptors, different individual subtype receptors are gaining interest as a potential biological target, through their ubiquity and variety of functions. Wilkinson et al focused on the P2X purinergic receptor 7, the P2X 7 R. P2X 7 R is a protein being composed of ion channels, which are cation selective and ligand gated, opening in response to ATP binding.…”

“…Unfortunately, the introduction of carboranes led to problematic solubility and the compounds showed no stability in aqueous solution, limiting biological investigations. The guanidyl- (35) and amidinyl-substituted carboranyl thymidine analogues (36) exhibited low phosphorylation rates (o30% relative to thymidine), in phosphoryl transfer assays. 36a and 36b showed 41900 and 41500 times better solubility in phosphate-buffered saline solutions than 34.…”

Ruthenacarborane–Phenanthroline Derivatives as Potential Metallodrugs

“…In order to design novel potential drugs, bioisosteric replacement has become a wide-spread approach [11,14,[19][20][21][22][23]. Thus, the development of drugs in which the carborane moiety mimics a phenyl group or is the pharmacophore itself is actively studied [23][24][25][26][27][28][29]. Applications of such carborane-containing drugs are for example cancer therapeutics and enzyme inhibitors [11,14,19,20,22,23,[30][31][32][33][34][35][36][37].…”

“…In order to design novel potential drugs, bioisosteric replacement has become a wide-spread approach [11,14,[19][20][21][22][23]. Thus, the development of drugs in which the carborane moiety mimics a phenyl group or is the pharmacophore itself is actively studied [23][24][25][26][27][28][29].…”

Molecular Modeling in Drug Design

“…Their study underlines the importance of not only filtering the virtual hits by predicting their aggregate forming potential computationally, but also of experimental assays for aggregation. The study by Vincenzi, Bednarska and Leśnikowski [7] highlights the current limitations of molecular docking programs. They developed a virtual screening protocol for adenosine derivatives that were substituted with either a boron cluster or a phenyl group.…”