Cheminformatics identification of modulators of key carbohydrate-metabolizing enzymes from C. cujete for type-2 diabetes mellitus intervention

Fatai Oladunni Balogun; Karishma Singh; Athika Rampadarath; Ayesha Akoonjee; Kayleen Naidoo; Saheed Sabiu

doi:10.1007/s40200-023-01249-7

Cheminformatics identification of modulators of key carbohydrate-metabolizing enzymes from C. cujete for type-2 diabetes mellitus intervention

J Diabetes Metab Disord. 2023 Jul 1;22(2):1299-1317. doi: 10.1007/s40200-023-01249-7. eCollection 2023 Dec.

Authors

Fatai Oladunni Balogun¹, Karishma Singh^{1

2}, Athika Rampadarath¹, Ayesha Akoonjee¹, Kayleen Naidoo¹, Saheed Sabiu¹

Affiliations

¹ Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, P.O. Box 1334, Durban, 4000 South Africa.
² Department of Nature Conservation, Mangosuthu University of Technology, Mangosuthu, South Africa.

Abstract

Purpose: The therapeutic use of oral hypoglycaemic agents in the management of type-2 diabetes mellitus (T2DM) is without adverse effects; thus, calls for alternative and novel candidates from natural products in medicinal plants.

Method: The study explored molecular docking and molecular dynamics (MD) simulation approaches to identify key antidiabetic metabolites from Crescentia cujete.

Results: Molecular docking results identified four and/or five best compounds against each target enzyme (alpha-glucosidase, dipeptidyl peptidase-IV, aldose reductase, and protein tyrosine phosphatase-1B (PTP-1B)) implicated in diabetes. The resulting complexes (except against PTP-1B) had higher docking scores above respective standards (acarbose, Diprotin A, ranirestat). The MD simulation results revealed compounds such as benzoic acid (-48.414 kcal/mol) and phytol (-45.112 kcal/mol) as well as chlorogenic acid (-42.978 kcal/mol) and naringenin (-31.292 kcal/mol) had higher binding affinities than the standards [acarbose (-28.248 kcal/mol), ranirestat (-21.042 kcal/mol)] against alpha-glucosidase and aldose reductase, respectively while Diprotin A (-45.112 kcal/mol) and ursolic acid (-18.740 kcal/mol) presented superior binding affinities than the compounds [luteolin (-41.957 kcal/mol and naringenin (-16.518 kcal/mol)] against DPP-IV and PTP-1B respectively.

Conclusion: While isoflavone (alpha-glucosidase), xylocaine (DPP-IV), luteolin (aldose reductase,) and chlorogenic acid (PTP-1B) were affirmed as the best inhibitors of respective enzyme targets, luteolin, and chlorogenic acid may be suggested and proposed as probable candidates against T2DM and related retinopathy complication based on their structural stability, compactness and affinity for three (DPP-IV, aldose reductase, and PTP-1B) of the four targets investigated. Further studies are warranted in vitro and in vivo on the antihyperglycaemic effects of these drug candidates.

Supplementary information: The online version contains supplementary material available at 10.1007/s40200-023-01249-7.

Keywords: Chlorogenic acid; Crescentia cujete; Isoflavone; Luteolin; Molecular dynamics simulation; Type-2 diabetes mellitus; Xylocaine.

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