Multidimensional Drug Design: Simultaneous Analysis of Binding and Relative Efficacy Profiles of N6-substituted-4¢-thioadenosines A3 Adenosine Receptor Agonists

Abstract

Desirability theory (DT) is a well-known multi-criteria decision-making approach. In this work, DT is employed as a prediction model (PM) interpretation tool to extract useful information on the desired trade-offs between binding and relative efficacy of N6-substituted-4¢-thioadenosines A3 adenosine receptor (A3AR) agonists. At the same time, it was shown the usefulness of a parallel but independent approach providing a feedback on the reliability of the combination of properties predicted as a unique desirability value. The appliance of belief theory allowed the quantification of the reliability of the predicted desirability of a compound according to two inverse and independent but complementary prediction approaches. This information is proven to be useful as a ranking criterion in a ligand-based virtual screening study. The development of a linear PM of the A3AR agonists overall desirability allows finding significant clues based on simple molecular descriptors. The model suggests a relevant role of the type of substituent on the N6 position of the adenine ring that in general contribute to reduce the flexibility and hydrophobicity of the lead compound. The mapping of the desirability function derived of the PM offers specific information such as the shape and optimal size of the N6 substituent. The model herein developed allows a simultaneous analysis of both binding and relative efficacy profiles of A3AR agonists. The information retrieved guides the theoretical design and assembling of a combinatorial library suitable for filtering new N6-substituted-4¢-thioadenosines A3AR agonist candidates with simultaneously improved binding and relative efficacy profiles. The utility of the desirability ⁄ belief-based proposed virtual screening strategy was deduced from our training set. Based on the overall results, it is possible to assert that the combined use of desirability and belief theories in computational medicinal chemistry research can aid the discovery of A3AR agonist candidates with favorable balance between binding and relative efficacy profiles.