The article describes the development of a robust pharmacophore model and the investigation of structure
activity relationship analysis of 46 xanthine derivatives reported for DPP-IV inhibition using PHASE module of
Schrodinger software. The present works also encompasses molecular interaction of 46 xanthine ligand through maestro
8.5 software. The QSAR study comprises AHHR.7 pharmacophore hypothesis, which elaborates the three points, e.g. one
hydrogen bond acceptor (A), two hydrophobic rings (H) and one aromatic ring (R). The discrete geometries as
pharmacophoric feature were developed and the generated pharmacophore model was used to derive a predictive atombased
3D QSAR model for the studied data set. The obtained 3D QSAR model has an excellent correlation coefficient
value (r2= 0.9995) along with good statistical significance which is indicated by high Fisher ratio (F= 8537.4). The model
also exhibits good predictive power confirmed by the high value of cross validated correlation coefficient (q2 = 0.6919).
The QSAR model suggests that hydrophobic character is crucial for the DPP-IV inhibitory activity exhibited by these
compounds and inclusion of hydrophobic substituents will enhance the DPP-IV inhibition. In addition to the hydrophobic
character, electron withdrawing groups positively contribute to the DPP-IV inhibition potency. The findings of the QSAR
study provide a set of guidelines for designing compounds with better DPP-IV inhibitory potency.
Keywords: DPP-IV inhibitors, docking, maestro, pharmacophore, PHASE, QSAR, Schrodinger, Xanthine, Lipinski’s rule-of-five theory.
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