DPP-4 inhibition mediated antidiabetic potential of phytoconstituents of an aqueous fruit extract of Withania coagulans (Stocks) Dunal: in-silico, in-vitro and in-vivo assessments

Abstract

The DPP-4 inhibition is an interesting target for the development of antidiabetic agents which promotes the longevity of GPL-1(Glucagon-like peptide 1). The current study was intended to assess DPP-4(Dipeptidyl Peptidase-4) inhibition mediated antidiabetic effect of phytocompounds of an aqueous fruit extract of Withania coagulans (Stocks) Dunal by in-vitro, in-silico and in-vivo approaches. The phytoconstituents screening was executed by LCMS (Liquid Chromatography with tandem mass spectrometry). The in-vitro and in-vivo, DPP-4 assays were performed by using available kits. The in-vitro DPP-4 activity was inhibited up to 68.3% by the test extract. Accordingly, in-silico determinations of molecular docking, molecular dynamics and pharmacokinetics were performed between the target enzyme DPP-4 and leading phytocompounds. The molecular dynamics authenticated the molecular docking data by crucial parameters of cytosolic milieu by the potential energy, RSMD (Root Mean Square Deviation), RSMF (Root Mean Square Fluctuation), system density, NVT (Number of particles at fixed volume, ensemble) and NPT (Number of particles at fixed pressure, ensemble). Accordingly, ADMET predictions assessed the druggability profile. Subsequently, the course of the test extract and the sitagliptin (positive control), instigated significant (p ≤ 0.001) ameliorations in HOMA indices and the equal of antioxidants in nicotinamide-streptozotocin induced type 2 diabetic animal model. Compassionately, the histopathology represented increased pancreatic cellular mass which caused in restoration of histoarchitectures. It has been concluded that phytoconstituents in W. coagulans aqueous fruit extract can regulate DPP-4, resulting in improved glucose homeostasis and enhanced endocrinal pancreatic cellular mass.

Communicated by Ramaswamy H. Sarma

KEYWORDS:

• Withania coagulans (Stocks) Dunal
• LCMS
• DPP-4 inhibition
• Phytoconstituents
• Type 2 diabetes
• molecular dynamics
• HOMA

Acknowledgement

Our team sincerely acknowledges the scientific discussion and help to identify the plant material by Dr. Mahendra Kumar Singhadiya, Scientist D, Reginal Centre, Botanical Survey of India, Jodhpur (Rajasthan), India. The authors would like to extend their sincere thanks to Prof. Elsayed Fathi Abd_Allah, Saud University, Riyadh, Saudi Arabia for his support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval

The Institutional Animal Ethical Committee (IAEC), Department of Zoology, JNVU, Jodhpur approved the protocols of current study as per CPCSEA norms (Reg. No.1646/GO/a/12/CPCSEA valid up to 27.03.23).

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Authors contributions

HR & BPS- Concept and Supervision, PKB & CA– In-silico investigation, PK- Phytochemistry, AK &AP Molecular Dynamisc, GS-Drafting & botanical Authentication,

PKB-Pramod Kumar, CK-Chandra Kala, CA-Charu Agnihotri, HR-Heera Ram, PK-Priya Kashyap, GS-Garima Singh, AK-Ashok Kumar, AP-Anil Panwar