Cheminformatics Identification of Modulators of Key Carbohydrate-metabolizing Enzymes from for Type-2 Diabetes Mellitus Intervention

Overview

Journal J Diabetes Metab Disord

Specialty Endocrinology

Date 2023 Nov 16

PMID 37969920

Authors

Fatai Oladunni Balogun

Karishma Singh

Athika Rampadarath

Ayesha Akoonjee

Kayleen Naidoo

Saheed Sabiu

Affiliations

Soon will be listed here.

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 .

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.

Citing Articles

Density functional theory and molecular dynamics simulation-based bioprospection of essential oil metabolites against protein tyrosine phosphatase 1B for interventive antidiabetic therapy.

Adedirin O, Abdulsalam R, Nasir-Naeem K, Oke A, Jubril A, Sabiu S Heliyon. 2025; 11(3):e42239.

PMID: 39991230 PMC: 11847251. DOI: 10.1016/j.heliyon.2025.e42239.

References

Zhao B, Le D, Hung Nguyen P, Ali M, Choi J, Min B . PTP1B, α-glucosidase, and DPP-IV inhibitory effects for chromene derivatives from the leaves of Smilax china L. Chem Biol Interact. 2016; 253:27-37. DOI: 10.1016/j.cbi.2016.04.012. View

Eawsakul K, Ongtanasup T, Ngamdokmai N, Bunluepuech K . Alpha-glucosidase inhibitory activities of astilbin contained in Bauhinia strychnifolia Craib. stems: an investigation by in silico and in vitro studies. BMC Complement Med Ther. 2023; 23(1):25. PMC: 9885589. DOI: 10.1186/s12906-023-03857-5. View

Seifert E . OriginPro 9.1: scientific data analysis and graphing software-software review. J Chem Inf Model. 2014; 54(5):1552. DOI: 10.1021/ci500161d. View

Cholko T, Chen W, Tang Z, Chang C . A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery. J Comput Aided Mol Des. 2018; 32(6):671-685. PMC: 6440799. DOI: 10.1007/s10822-018-0120-3. View

Salmaso V, Moro S . Bridging Molecular Docking to Molecular Dynamics in Exploring Ligand-Protein Recognition Process: An Overview. Front Pharmacol. 2018; 9:923. PMC: 6113859. DOI: 10.3389/fphar.2018.00923. View

Chen J, Wu S, Zhang Q, Yin Z, Zhang L . α-Glucosidase inhibitory effect of anthocyanins from Cinnamomum camphora fruit: Inhibition kinetics and mechanistic insights through in vitro and in silico studies. Int J Biol Macromol. 2019; 143:696-703. DOI: 10.1016/j.ijbiomac.2019.09.091. View

Cho N, Shaw J, Karuranga S, Huang Y, da Rocha Fernandes J, Ohlrogge A . IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018; 138:271-281. DOI: 10.1016/j.diabres.2018.02.023. View

Cherrak S, Merzouk H, Mokhtari-Soulimane N . Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: A molecular docking and simulation studies. PLoS One. 2020; 15(10):e0240653. PMC: 7561147. DOI: 10.1371/journal.pone.0240653. View

Zhang D, Lazim R . Application of conventional molecular dynamics simulation in evaluating the stability of apomyoglobin in urea solution. Sci Rep. 2017; 7:44651. PMC: 5353640. DOI: 10.1038/srep44651. View

10.

Babine R, Bender S . Molecular Recognition of Proteinminus signLigand Complexes: Applications to Drug Design. Chem Rev. 1997; 97(5):1359-1472. DOI: 10.1021/cr960370z. View

11.

Du X, Li Y, Xia Y, Ai S, Liang J, Sang P . Insights into Protein-Ligand Interactions: Mechanisms, Models, and Methods. Int J Mol Sci. 2016; 17(2). PMC: 4783878. DOI: 10.3390/ijms17020144. View

12.

Dodds S . The How-To for Type 2: An Overview of Diagnosis and Management of Type 2 Diabetes Mellitus. Nurs Clin North Am. 2017; 52(4):513-522. DOI: 10.1016/j.cnur.2017.07.002. View

13.

MubarakAli D, MohamedSaalis J, Sathya R, Irfan N, Kim J . An evidence of microalgal peptides to target spike protein of COVID-19: In silico approach. Microb Pathog. 2021; 160:105189. PMC: 8436434. DOI: 10.1016/j.micpath.2021.105189. View

14.

Huang P, Lin S, Chang C, Tsai M, Lee D, Weng C . Natural phenolic compounds potentiate hypoglycemia via inhibition of Dipeptidyl peptidase IV. Sci Rep. 2019; 9(1):15585. PMC: 6821704. DOI: 10.1038/s41598-019-52088-7. View

15.

Balogun F, Sabiu S . A Review of the Phytochemistry, Ethnobotany, Toxicology, and Pharmacological Potentials of L. (Bignoniaceae). Evid Based Complement Alternat Med. 2021; 2021:6683708. PMC: 8282368. DOI: 10.1155/2021/6683708. View

16.

Decherchi S, Cavalli A . Thermodynamics and Kinetics of Drug-Target Binding by Molecular Simulation. Chem Rev. 2020; 120(23):12788-12833. PMC: 8011912. DOI: 10.1021/acs.chemrev.0c00534. View

17.

Khan S, Fakhar Z, Hussain A, Ahmad A, Jairajpuri D, Alajmi M . Structure-based identification of potential SARS-CoV-2 main protease inhibitors. J Biomol Struct Dyn. 2020; 40(8):3595-3608. PMC: 7682383. DOI: 10.1080/07391102.2020.1848634. View

18.

Adinortey C, Kwarko G, Koranteng R, Boison D, Obuaba I, Wilson M . Molecular Structure-Based Screening of the Constituents of Identifies Potential Inhibitors of Diabetes Mellitus Target Alpha Glucosidase. Curr Issues Mol Biol. 2022; 44(2):963-987. PMC: 8928985. DOI: 10.3390/cimb44020064. View

19.

Karasu C, Cumaoglu A, Gurpinar A, Kartal M, Kovacikova L, Milackova I . Aldose reductase inhibitory activity and antioxidant capacity of pomegranate extracts. Interdiscip Toxicol. 2012; 5(1):15-20. PMC: 3389504. DOI: 10.2478/v10102-012-0003-8. View

20.

Branden G, Sjogren T, Schnecke V, Xue Y . Structure-based ligand design to overcome CYP inhibition in drug discovery projects. Drug Discov Today. 2014; 19(7):905-11. DOI: 10.1016/j.drudis.2014.03.012. View