Identification of a Novel Scaffold for Inhibition of Dipeptidyl Peptidase-4

Journal of Computational Biology : a Journal of Computational Molecular Cell Biology
Avinash MishraAbdul Sattar

Abstract

Dipeptidyl peptidase-4 (DPP-4) is considered a major drug target for type 2 diabetes mellitus (T2DM). In addition to T2DM, a regulatory role of DPP-4 was also found in cardiovascular diseases. Existing DPP-4 inhibitors have been reported to have several adverse effects. In this study, a computer-aided drug design approach and its use to detect a novel class of inhibitor for DPP-4 are reported. Through structure and pharmacophore-based screening, we identified 13 hit compounds from an ∼4-million-compound library. Physical interactions of these hits with DPP-4 were studied using docking and explicit solvent molecular dynamics (MD) simulations. Later, MMPBSA binding energy was calculated for the ligand/protein simulation trajectories to determine the stability of compounds in the binding cavity. These compounds have a novel scaffold and exhibited a stable binding mode. "Best-in-screen" compounds (or their closest available analogs) were resourced and their inhibition of DPP-4 activity was experimentally validated using an in vitro enzyme activity assay in the presence of 100 and 10 μM compounds. These assays identified a compound with a spirochromanone center with 53% inhibition activity at a 100 μM concentration. A further five s...Continue Reading

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Citations

Aug 25, 2021·Bioorganic & Medicinal Chemistry·Shubham KumarAmit Mittal

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Software Mentioned

HitGen
mmpbsa
[UNK]
GROMACS
MM
vHTS
PharmaGist
NovoDocker
ZincPharmer
PBSA

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