Discriminating between active and inactive compounds using binding energy calculations – a case study

Abstract

Xanthine oxidase inhibitors fall into two classes, those which co not (e.g. febuxostat). Recently we discovered a novel pyrimidine enzymatic assays. Molecular docking studies showed binding pattern similar to that of febuxostat. Shifting a nitrogen atom in pyrimidine ring (for convenience we will call them ‘reverse pyrimidine’ analogs), and docking to xanthine oxidase interactions and docking scores for the two chemotypes. However, the reverse pyrimidines showed loss of activity when tested enzymatic assay. As docking studies did not discriminate between the two scaffolds, in an effort to explain this u the enzymatic assay, MMGB-SA binding energy calculations were done on docked complexes. Detailed analysis of various contributing energy terms to deltaG values from MMGB-SA calculations indicated that the ‘ligand ~20 kcal/mol between pairs of pyrimidine and corresponding reverse pyrimidine derivatives. Ligand measure of stability of bound ligand to the protein active site. Higher values of this energy term chemotype, when bound in the receptor environment, has unfavorable contacts that may be responsible for the reduced activity compounds. From this study it can be inferred that MMGB studies do not provide expected results.