Exploring potency and selectivity receptor antagonist profiles using a multilabel classification approach: the human adenosine receptors as a key study.

Nowadays, in medicinal chemistry adenosine receptors represent some of the most studied targets, and there is growing interest on the different adenosine receptor (AR) subtypes. The AR subtypes selectivity is highly desired in the development of potent ligands to achieve the therapeutic success. So far, very few ligand-based strategies have been investigated to predict the receptor subtypes selectivity. In the present study, we have carried out a novel application of the multilabel classification approach by combining our recently reported autocorrelated molecular descriptors encoding for the molecular electrostatic potential (autoMEP) with support vector machines (SVMs). Three valuable models, based on decreasing thresholds of potency, have been generated as in series quantitative sieves for the simultaneous prediction of the hA(1)R, hA(2A)R, hA(2B)R, and hA(3)R subtypes potency profile and selectivity of a large collection, more than 500, of known inverse agonists such as xanthine, pyrazolo-triazolo-pyrimidine, and triazolo-pyrimidine analogues. The robustness and reliability of our multilabel classification models were assessed by predicting an internal test set. Finally, we have applied our strategy to 13 newly synthesized pyrazolo-triazolo-pyrimidine derivatives inferring their full adenosine receptor potency spectrum and hAR subtypes selectivity profile.