3D-Pharmacophore Models for Selective A_2Aand A_2BAdenosine Receptor Antagonists

Abstract

Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands.

Substructure‐Based Virtual Screening for Adenosine A2A Receptor Ligands

“…Interestingly, none of the tested compounds displayed binding at the A 2B AR. Consequently, selectivity of A 2A over A 2B , which is not considered trivial, [28] was reached. The same holds true for compounds with affinity for A 1 , where selectivity over A 2B was (unintentionally) reached.…”

Novel 8-(furan-2-yl)-3-substituted thiazolo [5,4-e][1,2,4] triazolo[1,5-c] pyrimidine-2(3H)-thione derivatives as potential adenosine A2A receptor antagonists

“…Synthesis of thiazolotriazolopyrimidine compounds (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) has been carried out according to Scheme 1. Concisely, the reaction of substituted isothiocyanate, triethylamine, sulfur and malononitrile was carried at 0-5°C for 1 h, then at room temperature for an hour to give the carbonitrile compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

“…To explicate the interaction of thiazolotriazolopyrimidine derivatives (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) (F168, E169), ECL3 (H 264, W268), TM5 (M174, M177) and TM6 (W246, L249, N253) domains. Docking simulation results showed that thiazolotriazolopyrimidine derivatives (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) and SCH58261 shared a similar binding motif inside the transmembrane (TM) region and extracellular loops of the human A 2A R similar to the co-crystallized ZM241385.…”

“…15 The pharmacophore model Hypo-A 2A established that minimal structural requirement features for A 2A R antagonistic activity and selectivity were aromatic ring (R), positively ionizable group (P), hydrophobicity (H), and hydrogen bond acceptor (L). 23 We replaced the pyrazole ring of SCH58261, a selective A 2A R antagonist by thiazole ring, and two categories of N-substituted thiazolotriazolopyrimidine derivatives were prepared, one with flexible up to 4-carbon homologation, and other substituted and unsubstituted planar aromatic ring to give compounds (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). In silico interaction of the compounds (23-33) with A 2A R was carried using autodock analysis.…”

Structural requirements for potential HIV-integrase inhibitors identified using pharmacophore-based virtual screening and molecular dynamics studies

“…It can also be used in virtual screening to identify potential molecules, predict the activity of the newly synthesized compound before animal experiment; or understand the possible mechanism of action 21,22 . In the current study, an attempt was made to identify the pharmacophore hypothesis using the …”