Structure-Based Screening of Uncharted Chemical Space for Atypical Adenosine Receptor Agonists.

Rodríguez D, Chakraborty S, Warnick E, Crane S, Gao ZG, O'Connor R, Jacobson KA, Carlsson J

ACS chemical biology 11 (10) 2763-2772 [2016-10-21; online 2016-08-22]

Small molecule screening libraries cover only a small fraction of the astronomical number of possible drug-like compounds, limiting the success of ligand discovery efforts. Computational screening of virtual libraries representing unexplored chemical space could potentially bridge this gap. Drug development for adenosine receptors (ARs) as targets for inflammation and cardiovascular diseases has been hampered by the paucity of agonist scaffolds. To identify novel AR agonists, a virtual library of synthetically tractable nucleosides with alternative bases was generated and structure-based virtual screening guided selection of compounds for synthesis. Pharmacological assays were carried out at three AR subtypes for 13 ribosides. Nine compounds displayed significant activity at the ARs, and several of these represented atypical agonist scaffolds. The discovered ligands also provided insights into receptor activation and revealed unknown interactions of endogenous and clinical compounds with the ARs. The results demonstrate that virtual compound databases provide access to bioactive matter from regions of chemical space that are sparsely populated in commercial libraries, an approach transferrable to numerous drug targets.

Affiliated researcher

Fellows programme

Jens Carlsson

PubMed 27439119

DOI 10.1021/acschembio.6b00357

Crossref 10.1021/acschembio.6b00357

pmc: PMC5207038
mid: NIHMS818598