title: In silico directed chemical probing of the adenosine receptor family.
abstract: One of the grand challenges in chemical biology is identifying a small-molecule modulator for each individual function of all human proteins. Instead of targeting one protein at a time, an efficient approach to address this challenge is to target entire protein families by taking advantage of the relatively high levels of chemical promiscuity observed within certain boundaries of sequence phylogeny. We recently developed a computational approach to identifying the potential protein targets of compounds based on their similarity to known bioactive molecules for almost 700 targets. Here, we describe the direct identification of novel antagonists for all four adenosine receptor subtypes by applying our virtual profiling approach to a unique synthesis-driven chemical collection composed of 482 biologically-orphan molecules. These results illustrate the potential role of in silico target profiling to guide efficiently screening campaigns directed to discover new chemical probes for all members of a protein family.
authors.affiliation: Center of Chemistry, Campus de Gualtar, Universidade do Minho, 4710-057 Braga, Portugal.
authors.forename: Filipe M
authors.initials: FM
authors.lastname: Areias
authors.forename: Jose
authors.initials: J
authors.lastname: Brea
authors.forename: Elisabet
authors.initials: E
authors.lastname: Gregori-Puigjané
authors.forename: Magdi E A
authors.initials: ME
authors.lastname: Zaki
authors.forename: M Alice
authors.initials: MA
authors.lastname: Carvalho
authors.forename: Eduardo
authors.initials: E
authors.lastname: Domínguez
authors.forename: Hugo
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
authors.forename: M Fernanda
authors.initials: MF
authors.lastname: Proença
authors.forename: María I
authors.initials: MI
authors.lastname: Loza
authors.forename: Jordi
authors.initials: J
authors.lastname: Mestres
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D016503:Drug Delivery Systems; D006801:Humans; D058915:Purinergic P1 Receptor Antagonists; D043704:Receptor, Adenosine A2B / Q000737:chemistry; D043684:Receptor, Adenosine A3 / Q000737:chemistry; D018047:Receptors, Purinergic P1 / Q000737:chemistry* / Q000145:classification*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D058915:Purinergic P1 Receptor Antagonists; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D054852:Small Molecule Libraries