Skip to content
2000
Volume 24, Issue 3
  • ISSN: 1871-5230
  • E-ISSN: 1875-614X

Abstract

Background

The presence of insufficient insulin signaling in type 2 diabetes arises due to either insulin resistance or impaired insulin secretion, ultimately leading to elevated blood glucose levels, a condition known as hyperglycemia. Diabetes poses a pervasive worldwide challenge, with its prevalence steadily surging in both developed and developing nations. A promising avenue for improving the management of diabetes type 2 involves the exploration of glucokinase activators as an innovative therapeutic target. Notably, a recent breakthrough in this area has been the market approval granted by the Japanese FDA for the use of the innovative GKA, Dorzagliatin, in the treatment of diabetes type 2.

Objectives

To augment the management of diabetes type 2 and mitigate the undesirable side effects linked to prolonged use of conventional medications, this research endeavor sought to create innovative glucokinase activators.

Methods

The ZINC database yielded a collection of 56 compounds, each showcasing a 40% structural similarity to 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid. These compounds, all featuring the distinctive indole core, were meticulously selected for further investigation. Structural illustrations were crafted using ChemBioDraw Ultra, and 1.5.6 AutoDock Vina was for molecular docking. The Swiss ADME algorithm facilitated online log P predictions, while the software PKCSM was utilized to forecast the toxicity profiles of the leading compounds. DFT analysis was done to ensure the stability of compounds by using Gaussian 16 quantum chemistry software and Mulliken charge distributions used to optimize molecular geometries.

Results

Among all the compounds, RS33 and RS37 exhibited the highest affinities for GK receptors, with the docking scores of -8.93 and -8.44 kcal/mol, respectively. These compounds follow Lipinski’s Rule, indicating promising absorption and excretion profiles through the gastrointestinal tract. Compared to standard drugs Dorzagliatin (GKA) and MRK (co-crystallized ligand), both RS33 and RS37 demonstrate no AMES toxicity, skin sensitization, and hepatotoxicity. RS43 is the most stable compound as it has high ΔE, η, and χ in DFT analysis.

Conclusion

The novel-designed lead molecules demonstrate an enhanced pharmacokinetic profile, superior binding affinity, and minimal toxicity, based on computational study. These attributes make them promising candidates for further optimization as glucokinase activators.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/aiaamc/10.2174/0118715230352441250309014403
2025-04-14
2025-09-26

  • From This Site

    /content/journals/aiaamc/10.2174/0118715230352441250309014403
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. MehraA. KumarS. MittalA. KohliR. MittalA. Insights to the emerging potential of glucokinase activators as antidiabetic agent.Pharm. Pat. Anal.2024131-3537110.1080/20468954.2024.2389762 39316577
     [Google Scholar]
  2. MehraA. Targeting diabetes with azole-derived medicinal agents.Med. Chem.202420985587510.2174/0115734064289990240524055002 38840402
     [Google Scholar]
  3. MehraA. MittalA. VishwakarmaP.K. Prediction of protein-drug interactions, pharmacophore modeling, and toxicokinetics of novel leads for type 2 diabetes treatment.Curr. Drug Metab.202425535538010.2174/0113892002321919240801065905 39108115
     [Google Scholar]
  4. MaccariR. WolberG. GenoveseM. SardelliG. TalagayevV. BalestriF. LutiS. SantiA. MoschiniR. Del CorsoA. PaoliP. OttanàR. Designed multiple ligands for the treatment of type 2 diabetes mellitus and its complications: Discovery of (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids active as novel dual-targeted PTP1B/AKR1B1 inhibitors.Eur. J. Med. Chem.202325211527010.1016/j.ejmech.2023.115270 36934484
     [Google Scholar]
  5. SharmaS. MittalA. MehraA. Oral insulin delivery: A patent review.Pharm. Pat. Anal.202211619921210.4155/ppa‑2022‑0017 36354044
     [Google Scholar]
  6. MingroneG. Castagneto-GisseyL. BornsteinS.R. New horizons: Emerging antidiabetic medications.J. Clin. Endocrinol. Metab.202210712e4333e434010.1210/clinem/dgac499 36106900
     [Google Scholar]
  7. HaileT.G. MariyeT. TadesseD.B. GebremeskelG.G. AsefaG.G. GetachewT. Prevalence of hypertension among type 2 diabetes mellitus patients in Ethiopia: A systematic review and meta-analysis.Int. Health202315323524110.1093/inthealth/ihac060 36055967
     [Google Scholar]
  8. CioanaM. DengJ. NadarajahA. HouM. QiuY. ChenS.S.J. RivasA. ToorP.P. BanfieldL. ThabaneL. ChaudharyV. SamaanM.C. Global prevalence of diabetic retinopathy in pediatric type 2 diabetes: A systematic review and meta-analysis.JAMA Netw. Open202363e23188710.1001/jamanetworkopen.2023.1887 36930156
     [Google Scholar]
  9. JensenE.T. RigdonJ. RezaeiK.A. SaaddineJ. LundeenE.A. DabeleaD. DolanL.M. D’AgostinoR.Jr KleinB. MeuerS. MeffordM.T. ReynoldsK. MarcovinaS.M. MottlA. Mayer-DavisB. LawrenceJ.M. Prevalence, progression, and modifiable risk factors for diabetic retinopathy in youth and young adults with youth-onset type 1 and type 2 diabetes: The SEARCH for diabetes in youth study.Diabetes Care20234661252126010.2337/dc22‑2503 37043887
     [Google Scholar]
  10. BjornstadP. ChaoL.C. Cree-GreenM. DartA.B. KingM. LookerH.C. MaglianoD.J. NadeauK.J. Pinhas-HamielO. ShahA.S. van RaalteD.H. PavkovM.E. NelsonR.G. Youth-onset type 2 diabetes mellitus: An urgent challenge.Nat. Rev. Nephrol.202319316818410.1038/s41581‑022‑00645‑1 36316388
     [Google Scholar]
  11. DucluzeauP.H. FauchierG. HerbertJ. SemaanC. HalimiJ.M. AngoulvantD. FauchierL. Prevalence and incidence of cardiovascular and renal diseases in type 1 compared with type 2 diabetes: A nationwide French observational study of hospitalized patients.Diabetes Metab.202349310142910.1016/j.diabet.2023.101429 36736892
     [Google Scholar]
  12. MaliniM. ThilagavathiR. Kumar SinghS. PravinA. SelvamC. Structure‐based drug design: Identification of glucokinase activators from natural compounds for the treatment of type 2 diabetes.ChemistrySelect2023815e20220490910.1002/slct.202204909
     [Google Scholar]
  13. DuttaD. KhandelwalD. KumarM. SharmaM. Efficacy and safety of novel dual glucokinase activator dorzagliatin in type-2 diabetes A meta-analysis.Diabetes Metab. Syndr.202317110269510.1016/j.dsx.2022.102695 36566614
     [Google Scholar]
  14. MaliniM. ThilagavathiR. VennilaJ. MalgijaB. PraveenaG. SelvamC. Identification of small-molecule glucokinase activator for type-2-diabetes treatment: A structure-based virtual screening approach.Mol. Simul.202349171596161310.1080/08927022.2023.2256425
     [Google Scholar]
  15. Anthony AmmalS.M. SudhaS. RajkumarD. BaskaranA. KrishnamoorthyG. AnbumozhiM.K. AmmalA. SudhaS. RajkumarD. KrishnamoorthyG. AnbumozhiM.K. In silico molecular docking studies of phytocompounds from Coleus amboinicus against glucokinase.Cureus2023152e3450710.7759/cureus.34507 36874339
     [Google Scholar]
  16. YangW. WuH. CaiX. LinC. JiaoR. JiL. Evaluation of efficacy and safety of glucokinase activators—a systematic review and meta-analysis.Front. Endocrinol. (Lausanne)202314117519810.3389/fendo.2023.1175198 37223016
     [Google Scholar]
  17. AshcroftF.M. LloydM. HaythorneE.A. Glucokinase activity in diabetes: Too much of a good thing?Trends Endocrinol. Metab.202334211913010.1016/j.tem.2022.12.007 36586779
     [Google Scholar]
  18. RemediM.S. NicholsC.G. Glucokinase inhibition: A novel treatment for diabetes?Diabetes202372217017410.2337/db22‑0731 36669001
     [Google Scholar]
  19. SharmaS. WadhwaK. ChoudharyM. BudhwarV. Ethnopharmacological perspectives of glucokinase activators in the treatment of diabetes mellitus.Nat. Prod. Res.202236112962297610.1080/14786419.2021.1931187 34044681
     [Google Scholar]
  20. RenY. LiL. WanL. HuangY. CaoS. Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists.J. Enzyme Inhib. Med. Chem.202237160661510.1080/14756366.2021.2025362 35067153
     [Google Scholar]
  21. SharmaP. SinghS. SharmaN. SinglaD. GuarveK. GrewalA.S. Targeting human Glucokinase for the treatment of type 2 diabetes: An overview of allosteric Glucokinase activators.J. Diabetes Metab. Disord.20222111129113710.1007/s40200‑022‑01019‑x 35673438
     [Google Scholar]
  22. AliA. Development of antidiabetic drugs from benzamide derivatives as glucokinase activator: A computational approach.Saudi J. Biol. Sci.20222953313332510.1016/j.sjbs.2022.01.058 35844378
     [Google Scholar]
  23. HamidA.A. Abdul-RasheedO.F. MahdiM.F. AtiaA.J. Design, synthesis, characterization, and biological evaluation of new diazole-benzamide derivatives as glucokinase activators with antihyperglycemic activity.Egypt. J. Chem.2022658451469
     [Google Scholar]
  24. KroonT. HagstedtT. AlexanderssonI. FermA. PeterssonM. MaurerS. ZarroukiB. WalleniusK. OakesN.D. BoucherJ. Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats.Sci. Transl. Med.202214668eabh131610.1126/scitranslmed.abh1316 36288279
     [Google Scholar]
  25. KleinK.R. BuseJ.B. A new class of drug in the diabetes toolbox.Nat. Med.202228590190210.1038/s41591‑022‑01783‑6 35551293
     [Google Scholar]
  26. YadavS. BhartiS. MathurP. GlucoKinaseDB: A comprehensive, curated resource of glucokinase modulators for clinical and molecular research.Comput. Biol. Chem.202310310781810.1016/j.compbiolchem.2023.107818 36680885
     [Google Scholar]
  27. MehraA. MittalA. SinghS. Molecular docking, pharmacophore modeling, and admet prediction of novel heterocyclic leads as glucokinase activators.Antiinflamm. Antiallergy Agents Med. Chem.2024Epub ahead of print. 39350548
     [Google Scholar]
  28. RajasF. Gautier-SteinA. MithieuxG. Glucose-6 phosphate, a central hub for liver carbohydrate metabolism.Metabolites201991228210.3390/metabo9120282 31756997
     [Google Scholar]
  29. MehraA. MittalA. ThakurD. Molecular docking, pharmacophore mapping, and virtual screening of novel glucokinase activators as antidiabetic agents.Curr. Proteomics202421425127610.2174/0115701646323264240821072359
     [Google Scholar]
  30. SternishaS.M. MillerB.G. Molecular and cellular regulation of human glucokinase.Arch. Biochem. Biophys.201966319921310.1016/j.abb.2019.01.011 30641049
     [Google Scholar]
  31. CoghlanM. LeightonB. Glucokinase activators in diabetes management.Expert Opin. Investig. Drugs200817214516710.1517/13543784.17.2.145 18230050
     [Google Scholar]
  32. ThilagavathiR. Hosseini-ZareM.S. MaliniM. SelvamC. A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes.Chem. Biol. Drug Des.202299224726310.1111/cbdd.13979 34714587
     [Google Scholar]
  33. PalM. Recent advances in glucokinase activators for the treatment of type 2 diabetes.Drug Discov. Today20091415-1678479210.1016/j.drudis.2009.05.013 19520181
     [Google Scholar]
  34. HaddadD. DsouzaV.S. Al-MullaF. Al MadhounA. New-generation glucokinase activators: Potential game-changers in type 2 diabetes treatment.Int. J. Mol. Sci.202425157110.3390/ijms25010571 38203742
     [Google Scholar]
  35. MatschinskyF.M. Assessing the potential of glucokinase activators in diabetes therapy.Nat. Rev. Drug Discov.20098539941610.1038/nrd2850 19373249
     [Google Scholar]
  36. PaliwalA. PaliwalV. JainS. PaliwalS. SharmaS. Current insight on the role of glucokinase and glucokinase regulatory protein in diabetes.Mini Rev. Med. Chem.202424767468810.2174/1389557523666230823151927 37612862
     [Google Scholar]
  37. KaziA.A. ChatpalliwarV.A. Design, synthesis, molecular docking and in vitro biological evaluation of benzamide derivatives as novel glucokinase activators.Curr. Enzym. Inhib.2022181617510.2174/1573408018666220218093451
     [Google Scholar]
  38. MehraA. MehraA. Antidiabetic advancements in silico: Pioneering novel heterocyclic derivatives through computational design.Curr. Signal Transduct. Ther.2024192e24042422925410.2174/0115743624282326240418104054
     [Google Scholar]
  39. Al AzzamK.M. NegimE.S. Aboul-EneinH.Y. ADME studies of TUG-770 (a GPR-40 inhibitor agonist) for the treatment of type 2 diabetes using SwissADME predictor: In silico study.J. Appl. Pharm. Sci.2022124159169
     [Google Scholar]
  40. MehraA. WadhwaP. MittalA. MehraA. Molecular design and virtual screening of novel heterocyclic derivatives as Glucokinase activators. Turkish.Comp. Theo. Chem.202483749810.33435/tcandtc.1386285
     [Google Scholar]
  41. KamataK. MitsuyaM. NishimuraT. EikiJ. NagataY. Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase.Structure200412342943810.1016/j.str.2004.02.005 15016359
     [Google Scholar]
  42. TaherkhaniA. OrangiA. MoradkhaniS. KhamverdiZ. Molecular docking analysis of flavonoid compounds with matrix metalloproteinase-8 for the identification of potential effective inhibitors.Lett. Drug Des. Discov.2021181164510.2174/1570180817999200831094703
     [Google Scholar]
  43. SouzaP.F.N. LopesF.E.S. AmaralJ.L. FreitasC.D.T. OliveiraJ.T.A. A molecular docking study revealed that synthetic peptides induced conformational changes in the structure of SARS-CoV-2 spike glycoprotein, disrupting the interaction with human ACE2 receptor.Int. J. Biol. Macromol.2020164667610.1016/j.ijbiomac.2020.07.174 32693122
     [Google Scholar]
  44. FrischM.J. TrucksG.W. SchlegelH.B. ScuseriaG.E. RobbM.A. CheesemanJ.R. ScalmaniG. BaroneV.P. PeterssonG.A. NakatsujiH.J. LiX. Gaussian 16 revision C. 01, 2016.Gaussian Inc. Wallingford CT.20161572
     [Google Scholar]
  45. DasN.C. LabalaR.K. PatraR. ChattorajA. MukherjeeS. In silico identification of new anti-SARS-CoV-2 agents from bioactive phytocompounds targeting the viral spike glycoprotein and human TLR4.Lett. Drug Des. Discov.202219317519110.2174/1570180818666210901125519
     [Google Scholar]
/content/journals/aiaamc/10.2174/0118715230352441250309014403
Loading
Inclusive Drug Designing of Novel Indole Derivatives using Rationale, Pharmacophore Mapping and Molecular Docking
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) 24, 179 (2025); https://doi.org/10.2174/0118715230352441250309014403
/content/journals/aiaamc/10.2174/0118715230352441250309014403
/content/journals/aiaamc/10.2174/0118715230352441250309014403
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): binding affinity; diabetes; docking; Glucokinase activators; indole derivatives; SAR

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test