Structure–Activity Relationship and Molecular Docking of Natural Product Library Reveal Chrysin as a Novel Dipeptidyl Peptidase-4 (DPP-4) Inhibitor: An Integrated In Silico and In Vitro Study

Abstract

Numerous studies indicate that diets with a variety of fruits and vegetables decrease the incidence of severe diseases, like diabetes, obesity, and cancer. Diets contain a variety of bioactive compounds, and their features, like diverge scaffolds, and structural complexity make them the most successful source of potential leads or hits in the process of drug discovery and drug development. Recently, novel serine protease dipeptidyl peptidase-4 (DPP-4) inhibitors played a role in the management of diabetes, obesity, and cancer. This study describes the development of field template, field-based qualitative structure–activity relationship (SAR) model demonstrating DPP-4 inhibitors of natural origin, and the same model is used to screen virtually focused food database composed of polyphenols as potential DPP-4 inhibitors. Compounds’ similarity to field template, and novelty score “high and very high”, were used as primary criteria to identify novel DPP-4 inhibitors. Molecular docking simulations were performed on the resulting natural compounds using FlexX algorithm. Finally, one natural compound, chrysin, was chosen to be evaluated experimentally to demonstrate the applicability of constructed SAR model. This study provides the molecular insights necessary in the discovery of new leads as DPP-4 inhibitors, to improve the potency of existing DPP-4 natural inhibitors.

Phytochemicals in Garlic Extract Inhibit Therapeutic Enzyme DPP-4 and Induce Skeletal Muscle Cell Proliferation: A Possible Mechanism of Action to Benefit the Treatment of Diabetes Mellitus

“…Since it was already proven that garlic extract inhibits DPP-4, and the main compounds in this extract are the ones mentioned above, this led us to hypothesize that these phytochemicals could probably inhibit DPP-Among these compounds, polyphenol catechin was already proven to inhibit DPP-4 [65]. To understand the potential DPP-4 inhibition of the remaining identified phytochemicals in garlic extract, in silico methodologies such as field-based virtual screening and molecular docking simulations were carried out based on our earlier works [44,66], where the qualitative structure-activity relationship model of DPP-4 inhibitors was constructed and validated experimentally. The prebuilt QSAR model was utilized to demonstrate the potential DPP-4 inhibition capacity of the identified phytochemicals in garlic bulb extract.…”

“…Results revealed all the chemicals maintained a novelty score of very high, and Table 1 shows the similarity score of the identified phytochemicals predicted by the QSAR model for DPP-4 inhibition. The activity cliff summary of positive and negative electrostatic features of the identified phytochemicals such as the DPP-4 inhibitor is shown in Figure 7, compared to already-built QSAR features of DPP-4 inhibition [44,66]. The red color site represents positive electrostatics features, and blue color denotes negative electrostatic features of DPP-4 inhibition.…”

“…In our earlier study [44], the activity atlas model of DPP-4 inhibitors was constructed and validated using Forge software (Cresset Inc., Cambridgeshire, UK). This model was utilized to understand the features of phytochemicals identified in the garlic bulb extract as possible DPP-4 inhibitors.…”

An Integrated In Silico and In Vitro Assays of Dipeptidyl Peptidase-4 and α-Glucosidase Inhibition by Stellasterol from Ganoderma australe

“…Kalhotra et al [30,31] examined the profile for the addition of hydroxyl groups to inhibit the DPP-4 enzyme. Their results showed that galangin (a flavonoid with two hydroxyl groups) gives higher inhibition than chrysin (a flavonoid with two hydroxyl groups).…”

Design and Molecular dynamic Investigations of 7,8-Dihydroxyflavone Derivatives as Potential Neuroprotective Agents Against Alpha-synuclein

“…Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties of DHF derivative molecules were analyzed using Accelery Discovery Studio (DS) 3.5 41,42 . Further, the docking studies were carried out using Biosolve IT (Lead IT) software package 43 and Desmond v3.6 Package was used to run the MD simulation. The intermolecular interactions were analyzed using Pymol and Chimera 44,45 .…”