Title:3D QSAR and Docking Studies of Various Amido and Benzyl-substituted 3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl Analogs as DPP-IV Inhibitors
Volume: 20
Issue: 9
Author(s): Ritesh Agrawal, Pratima Jain, Subodh Narayan Dikshit and Sourabh Jain
Affiliation:
Keywords:
3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl analogs, docking, DPP-IV inhibitors, mestro, Optimum Polarized
Ligand Simulation-2005 (OPLS-2005), pharmacophore, PHASE, QSAR, schrodinger.
Abstract: The article describes the development of a robust pharmacophore model and the investigation of structure activity
relationship analysis of 3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl analogs reported for DPP-IV inhibition using
PHASE module of Schrodinger software. The present works also encompass molecular interaction study of 3-amino-4-(2-
cyanopyrrolidide)pyrrolidinyl analogs on maestro 8.5 workstation. The Phase study module comprises the five points
pharmacophore model (AAHPR.617), consisting two hydrogen bond acceptor (A), one Hydrophobic (H), one Positive(P)
and one aromatic ring (R) and with discrete geometries as pharmacophoric feature. The developed pharmacophore model
was used to derive a predictive atom-based 3D QSAR model. The obtained 3D QSAR model has an excellent correlation
coefficient value (r2=0.9926) along with good statistical significance as shown by high Fisher ratio (F=671.7). The model
also exhibits good predictive power, which is confirmed by high value of cross validated correlation coefficient (q2 =
0.7311). The QSAR model suggests that hydrophobic and aromatic characters are crucial for the DPP-IV inhibitory activity.
The QSAR model also suggests that the inclusion of hydrophobic substituents would enhance the DPP-IV inhibition.
In addition to the hydrogen bond acceptor, hydrophobic character, electro withdrawing character positively contributes to
the DPP-IV inhibition. This study provides a set of guidelines for designing compounds with better DPP-IV inhibitory potency.
