Molecular dynamic simulations reveal the mechanism of binding between xanthine inhibitors and DPP-4

Abstract

We apply molecular docking, molecular dynamics (MD) simulation, and binding free energy calculation to investigate and reveal the binding mechanism between five xanthine inhibitors and DPP-4. The electrostatic and van der Waals interactions of the five inhibitors with DPP-4 are analyzed and discussed. The computed binding free energies using MM-PBSA method are in qualitatively agreement with experimental inhibitory potency of five inhibitors. The hydrogen bonds of inhibitors with Ser630 and Asp663 can stabilize the inhibitors in binding sites. The van der Waals interactions, especially the key contacts with His740, Asn710, Trp629, and Tyr666 have larger contributions to the binding free energy and play important roles in distinguishing the variant bioactivity of five inhibitors.

Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor

“…However, whether the two specific water molecules are necessary for an inhibitor to maintain stable binding with DPP-4 should be confirmed by a solution structure using nuclear magnetic resonance (NMR) or molecular dynamics simulation (the solution structure of DPP-4 has not yet been obtained using NMR). A few molecular dynamics simulations have reported the interaction between DPP-4 and its inhibitor [ 79 , 80 ], but further simulations evaluating hydrated water require additional research, which we plan to perform in the future.…”

Design and characterization of antithrombotic ClEKnsTy-Au nanoparticles as diagnostic and therapeutic reagents

“…The average of results from three parallel simulations was taken for analysis. The binding free energy was calculated by the protocol that used in the literature 37,38 and our previous work. 16,18,19,39–41 The equations were described briefly as follows.Δ G bind = Δ G polar + Δ G nonpolar Δ G polar = Δ G elec + Δ G PB Δ G nonpolar = Δ G vdW + Δ G SASA …”

“…Then the relative free energy was calculated without consideration of the entropy term as that in the literature. 37,38…”

Recent Developments and Applications of the MMPBSA Method

“…For inflammatory disorders, targets such as COX-2 (Chaudhary and Aparoy, 2017 ), interleukin 6 (Verma R. et al, 2016 ), toll-like receptors (Shen et al, 2016 ), human leukocyte antigen (Kongkaew et al, 2015 ), chymase enzyme (Verma et al, 2017 ), tumor necrosis factor (Ivanisenko et al, 2014 ), and Nalp3 (Sahoo et al, 2014b ) were studied. For diabetes, analyses of targets included phosphorylase kinase (Begum et al, 2015 ), glycogen synthase kinase (Arfeen et al, 2015 ), protein kinase C beta II (Grewal and Sobhia, 2014 ), and dipeptidyl peptidase-4 enzyme (Gu et al, 2014 ; Sneha and Doss, 2016 ). In a search for compounds for the treatment of chronic kidney disease, Vitamin D receptor and cytochrome P450 were analyzed (Nagamani et al, 2016 ).…”