Cheminformatics Identification and Validation of Dipeptidyl Peptidase-IV Modulators from Shikimate Pathway-Derived Phenolic Acids towards Interventive Type-2 Diabetes Therapy

Abstract

Recently, dipeptidyl peptidase-IV (DPP-IV) has become an effective target in the management of type-2 diabetes mellitus (T2D). The study aimed to determine the efficacy of shikimate pathway-derived phenolic acids as potential DPP-IV modulators in the management of T2D. The study explored in silico (molecular docking and dynamics simulations) and in vitro (DPP-IV inhibitory and kinetics assays) approaches. Molecular docking findings revealed chlorogenic acid (CA) among the examined 22 phenolic acids with the highest negative binding energy (−9.0 kcal/mol) showing a greater affinity for DPP-IV relative to the standard, Diprotin A (−6.6 kcal/mol). The result was corroborated by MD simulation where it had a higher affinity (−27.58 kcal/mol) forming a more stable complex with DPP-IV than Diprotin A (−12.68 kcal/mol). These findings were consistent with in vitro investigation where it uncompetitively inhibited DPP-IV having a lower IC50 (0.3 mg/mL) compared to Diprotin A (0.5 mg/mL). While CA showed promising results as a DPP-IV inhibitor, the findings from the study highlighted the significance of medicinal plants particularly shikimate-derived phenolic compounds as potential alternatives to synthetic drugs in the effective management of T2DM. Further studies, such as derivatisation for enhanced activity and in vivo evaluation are suggested to realize its full potential in T2D therapy.

Insights into the Mechanism of Action of Helianthus annuus (Sunflower) Seed Essential Oil in the Management of Type-2 Diabetes Mellitus Using Network Pharmacology and Molecular Docking Approaches

“…The use of medicinal plants is a laudable approach and widely accepted in recent times due to its desired therapeutic effect. However, these plants containing one or more bioactive components might present a difficult task if their mechanisms of action are yet to be determined [46]. Hence, to simplify this possible complicated process, the exploration of network-pharmacology-aided molecular docking approaches may go a long way in achieving this task.…”

“…The type and number of interactions resulting in complex formation from the binding of ligand and the protein's amino acid residues is not only a consequence of eventual affinity [69], but essential in the development of a probable drug candidate [70]. A complex with a higher number of interactions often presents profound complex stability; the presence of important bonds such as H bonds and van der Waals bonds [46,71] as well as the shorter bond length existing between amino acid residues [72] are also important elements that contribute to a stronger affinity (between ligands and proteins). Intriguingly, the presence of interactions such as van der Waal forces, pi-pi stacked, and H bonds predominant between the top five active compounds and respective receptor target proteins as found in this study could be said to be indicative of their importance and possibly the well-established complex stability (of some of them) compared with to the used references.…”

“…The presence (and number) of H bonds is one of the key factors in conferring complex stability, as there are reports that H bonds contribute largely to the stability of complexes [46,67]. The lack of higher numbers of interactions of linoleic acid-FABP4 complexes, despite their high docking scores relative to tricosylic acid-FABP4, may be a result of their lower number of H bonds and other interactions (alkyl and/or pi-alkyl groups) since a higher number of H bonds contributes to the affinity and overall stability of the complex [71].…”

Natural products from plants targeting key enzymes for the future development of antidiabetic agents

“…76 Chlorogenic acid (80), a polyphenol widely distributed in plants, is the only uncompetitive inhibitor reported in this group of compounds. 66,67 It also normalized the metabolism of glucose and lipids by increasing the expression of GLUT-4 by different mechanisms including inhibition of G6Pase and suppressing glucose transport in the intestine. Gallic acid (83) also reduced triglyceride and total cholesterol.…”

“…Representative DPP-IV inhibitory flavonoids ( 1–72 ) and other aromatic compounds ( 73–100 ) are summarized in Table 1. 42–71 …”