Abstract
The dipeptidyl peptidase-IV (DPP-IV) family of receptors possesses a large binding cavity that imparts promiscuity for number of ligand binding which is not common to other receptors. This feature increases the challenge of using computational methods to identify DPP-IV inhibitors, therefore using both pharmacophore and structure-based screening seems to be a reliable approach. Mining of novel DPP-IV inhibitors by integrating both of these in silico techniques was reported. Pharmacophore model (Model_008) obtained from structurally diverse reported compounds was used as a template for screening of MolMall database followed by structure-based screening against PDB ID: 5T4E. After absorption, distribution, metabolism and excretion (ADME) analysis of shortlisted compounds, consensus docking and molecular mechanics/generalized born surface area studies were carried out. The results of the docking studies obtained were comparable to that of the reference ligand. Out of nine hits identified, only one hit (ID MolMall-20062) was available which was procured through exchange program. Molecular dynamic simulation studies of the procured hit revealed its good selectivity and stability in DPP-IV binding pocket and interactions observed with important amino acids viz., Trp629, Lys544 and Arg125. Biological testing of the compound MolMall-20062 showed promising DPP-IV inhibition activity with IC
50
: 6.2 µM. Compound MolMall-20062 could be taken as a good lead for the development of DPP-IV inhibitors.
Abbreviations
ADME
absorption, distribution, metabolism and excretion
ChEBI
chemical entities of biological interest
DPP-IV
dipeptidyl peptidase IV
DISCOtech
distance comparisons
HTVS
high throughput virtual screening
MD
molecular dynamics
MM-GBSA
molecular mechanics-generalized born surface area
OGTT
oral glucose tolerance test
PBVS
pharmacophore-based virtual screening
PDB
protein data bank
RMSD
root mean square deviation
ROC
receiver operating characteristics
SP
standard precision
SBVS
structure-based virtual screening
VS
virtual screening
XP
extra precision
Communicated by Ramaswamy H. Sarma