Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Letters in Drug Design & Discovery
  4. Volume 21, Issue 17
  5. Article
Volume 21, Issue 17
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

Inflammation is an immunological reaction against an aggressor agent. NLRP3 inflammasome is a component of the immune system, which, when excessively activated, results in several inflammatory diseases, making it an attractive target for discovering anti-inflammatory drugs. Computer-Aided Drug Design (CADD) techniques are powerful tools used to search for new drugs in less time and financial cost. Recently, studies demonstrated the CADD methods to discover information about NLRP3 inhibitors and . In addition, the discovery of and its evaluation in clinical trials instigate new studies to find binding modes and structural attributes that can used in drug design works against this target.

Objective

Here, molecular modeling methods were used to discover the significant interactions of , , and with NLRP3 to obtain helpful information in drug design compared to other inhibitors.

Methods

Molecular docking was performed using GOLD software. The best complexes were submitted into molecular dynamics simulations using GROMACS software, and the MM-PBSA was used to provide the free binding energy, which was performed using the tool compiled in GROMACS.

Results

The RMSD, RMSF, R, SASA, and H-bond plots showed that the compound was stable during MD simulation time (100 ns) for . The PCA analysis for all compounds verified similar variance of the complex with the inhibitors to the apo-NLRP3, indicative of stability. DCCM analysis showed the best correlation in residues 134 - 371 region, which contains critical amino acids from the binding site (Ala227, Ala228, and Arg578), besides the newly identified residues. Using MM-PBSA to provide the binding free energy, it was observed that the high affinity of the drugs against NLRP3 is related to the lower rigidity of the structure. Furthermore, we identified the critical residues Phe575, Pro352, Tyr632, and Met661 related to the coupling process.

Conclusion

Thus, these discoveries may contribute to the development of new anti-inflammatory drugs, such as NLRP3 inhibitors.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/lddd/10.2174/0115701808303890240620074039
2024-06-28
2025-05-12

  • From This Site

    /content/journals/lddd/10.2174/0115701808303890240620074039
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. dos Santos NascimentoI.J. de AquinoT.M. da Silva JúniorE.F. Computer-aided drug design of anti-inflammatory agents targeting microsomal prostaglandin E 2 synthase-1 (mPGES-1).Curr. Med. Chem.202229335397541910.2174/092986732966622031712294835301943
     [Google Scholar]
  2. dos Santos NascimentoI.J. da Silva-JúniorE.F. TNF-α inhibitors from natural compounds: An overview, CADD approaches, and their exploration for anti-inflammatory agents.Comb. Chem. High Throughput Screen.20212410.2174/138620732466621071516594334269666
     [Google Scholar]
  3. BonhommeD. SantecchiaI. Vernel-PauillacF. CaroffM. GermonP. MurrayG. AdlerB. BonecaI.G. WertsC. Correction: Leptospiral LPS escapes mouse TLR4 internalization and TRIF-associated antimicrobial responses through O antigen and associated lipoproteins.PLoS Pathog.20201612e100917310.1371/journal.ppat.100917333362240
     [Google Scholar]
  4. HotamisligilG.S. Inflammation, metaflammation and immunometabolic disorders.Nature2017542764017718510.1038/nature2136328179656
     [Google Scholar]
  5. BjarnasonI. ScarpignatoC. HolmgrenE. OlszewskiM. RainsfordK.D. LanasA. Mechanisms of damage to the gastrointestinal tract from nonsteroidal anti-inflammatory drugs.Gastroenterology2018154350051410.1053/j.gastro.2017.10.04929221664
     [Google Scholar]
  6. ArfèA. ScottiL. Varas-LorenzoC. NicotraF. ZambonA. KollhorstB. SchinkT. GarbeE. HeringsR. StraatmanH. SchadeR. VillaM. LucchiS. ValkhoffV. RomioS. ThiessardF. SchuemieM. ParienteA. SturkenboomM. CorraoG. Safety of Non-steroidal Anti-inflammatory Drugs (SOS) Project Consortium Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: Nested case-control study.BMJ2016354i485710.1136/bmj.i485727682515
     [Google Scholar]
  7. MarcénB. SostresC. LanasA. AINE and riesgo digestivo.Aten. Primaria2016482737610.1016/j.aprim.2015.04.00826857654
     [Google Scholar]
  8. RhenT. CidlowskiJ.A. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs.N. Engl. J. Med.2005353161711172310.1056/NEJMra05054116236742
     [Google Scholar]
  9. McDonoughA.K. CurtisJ.R. SaagK.G. The epidemiology of glucocorticoid-associated adverse events.Curr. Opin. Rheumatol.200820213113710.1097/BOR.0b013e3282f5103118349741
     [Google Scholar]
  10. WangD. HaileA. JonesL.C. Dexamethasone-induced lipolysis increases the adverse effect of adipocytes on osteoblasts using cells derived from human mesenchymal stem cells.Bone201353252053010.1016/j.bone.2013.01.00923328495
     [Google Scholar]
  11. SingerM. DeutschmanC.S. SeymourC.W. Shankar-HariM. AnnaneD. BauerM. BellomoR. BernardG.R. ChicheJ.D. CoopersmithC.M. HotchkissR.S. LevyM.M. MarshallJ.C. MartinG.S. OpalS.M. RubenfeldG.D. van der PollT. VincentJ.L. AngusD.C. The third international consensus definitions for sepsis and septic shock (Sepsis-3).JAMA2016315880181010.1001/jama.2016.028726903338
     [Google Scholar]
  12. JieF. XiaoS. QiaoY. YouY. FengY. LongY. LiS. WuY. LiY. DuQ. Kuijieling decoction suppresses NLRP3-Mediated pyroptosis to alleviate inflammation and experimental colitis in vivo and in vitro.J. Ethnopharmacol.202126411324310.1016/j.jep.2020.11324332781258
     [Google Scholar]
  13. RiusJ. GumaM. SchachtrupC. AkassoglouK. ZinkernagelA.S. NizetV. JohnsonR.S. HaddadG.G. KarinM. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α.Nature2008453719680781110.1038/nature0690518432192
     [Google Scholar]
  14. ChenJ. ChenZ.J. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation.Nature20185647734717610.1038/s41586‑018‑0761‑330487600
     [Google Scholar]
  15. SharifH. WangL. WangW.L. MagupalliV.G. AndreevaL. QiaoQ. HauensteinA.V. WuZ. NúñezG. MaoY. WuH. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome.Nature2019570776133834310.1038/s41586‑019‑1295‑z31189953
     [Google Scholar]
  16. GrebeA. HossF. LatzE. NLRP3 inflammasome and the IL-1 pathway in atherosclerosis.Circ. Res.2018122121722174010.1161/CIRCRESAHA.118.31136229880500
     [Google Scholar]
  17. MilnerM.T. MaddugodaM. GötzJ. BurgenerS.S. SchroderK. The NLRP3 inflammasome triggers sterile neuroinflammation and Alzheimer’s disease.Curr. Opin. Immunol.20216811612410.1016/j.coi.2020.10.01133181351
     [Google Scholar]
  18. ZhenY. ZhangH. NLRP3 inflammasome and inflammatory bowel disease.Front. Immunol.20191027610.3389/fimmu.2019.0027630873162
     [Google Scholar]
  19. ChenX. ZhangD. LiY. WangW. BeiW. GuoJ. NLRP3 inflammasome and IL-1β pathway in type 2 diabetes and atherosclerosis: Friend or foe?Pharmacol. Res.202117310588510.1016/j.phrs.2021.10588534536551
     [Google Scholar]
  20. AbbateA. ToldoS. MarchettiC. KronJ. Van TassellB.W. DinarelloC.A. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease.Circ. Res.202012691260128010.1161/CIRCRESAHA.120.31593732324502
     [Google Scholar]
  21. ManganM.S.J. OlhavaE.J. RoushW.R. SeidelH.M. GlickG.D. LatzE. Targeting the NLRP3 inflammasome in inflammatory diseases.Nat. Rev. Drug Discov.201817858860610.1038/nrd.2018.9730026524
     [Google Scholar]
  22. KolbR. LiuG.H. JanowskiA.M. SutterwalaF.S. ZhangW. Inflammasomes in cancer: A double-edged sword.Protein Cell201451122010.1007/s13238‑013‑0001‑424474192
     [Google Scholar]
  23. Dos Santos NascimentoI.J. Santana GomesJ.N. de Oliveira VianaJ. de Medeiros E SilvaY.M.S. BarbosaE.G. de MouraR.O. The power of molecular dynamics simulations and their applications to discover cysteine protease inhibitors.Mini Rev. Med. Chem.20232310.2174/138955752366623090115225737680157
     [Google Scholar]
  24. NascimentoI.J.S. de AquinoT.M. da Silva-JúniorE.F. The new era of drug discovery: The power of computer-aided drug design (CADD).Lett. Drug Des. Discov.2022191195195510.2174/1570180819666220405225817
     [Google Scholar]
  25. dos Santos NascimentoI.J. de AquinoT.M. da Silva-JúniorE.F. Drug repurposing: A strategy for discovering inhibitors against emerging viral infections.Curr. Med. Chem.202128152887294210.2174/1875533XMTA5rMDYp532787752
     [Google Scholar]
  26. NascimentoI.J dos S. Structure-based drug discovery approaches applied to SARS-CoV-2 (COVID-19).Pharmaceuticals for Targeting CoronavirusesBentham science202216110.2174/9789815051308122010003
     [Google Scholar]
  27. dos Santos NascimentoI.J. da Silva RodriguesÉ.E. da SilvaM.F. de Araújo-JúniorJ.X. de MouraR.O. Advances in computational methods to discover new ns2b-ns3 inhibitors useful against dengue and zika viruses.Curr. Top. Med. Chem.202222292435246210.2174/156802662366622112212133036415099
     [Google Scholar]
  28. NascimentoI.J.S. CavalcantiM.A.T. de MouraR.O. Exploring N-myristoyltransferase as a promising drug target against parasitic neglected tropical diseases.Eur. J. Med. Chem.202325811555010.1016/j.ejmech.2023.11555037336067
     [Google Scholar]
  29. dos Santos NascimentoI.J. da Silva-JúniorE.F. de AquinoT.M. Molecular modeling targeting transmembrane serine protease 2 (TMPRSS2) as an alternative drug target against coronaviruses.Curr. Drug Targets20212210.2174/138945012266621080909090934370633
     [Google Scholar]
  30. NiuY. LinP. Advances of computer-aided drug design (CADD) in the development of anti-Azheimer’s-disease drugs.Drug Discov. Today202328810366510.1016/j.drudis.2023.10366537302540
     [Google Scholar]
  31. GuptaA. ChaudharyN. AparoyP. MM-PBSA and per-residue decomposition energy studies on 7-Phenyl-imidazoquinolin-4(5H)-one derivatives: Identification of crucial site points at microsomal prostaglandin E synthase-1 (mPGES-1) active site.Int. J. Biol. Macromol.201811935235910.1016/j.ijbiomac.2018.07.05030031079
     [Google Scholar]
  32. AjalaA. UzairuA. ShallangwaG.A. AbechiS.E. Virtual screening, molecular docking simulation and ADMET prediction of some selected natural products as potential inhibitors of NLRP3 inflammasomes as drug candidates for Alzheimer disease.Biocatal. Agric. Biotechnol.20234810261510.1016/j.bcab.2023.102615
     [Google Scholar]
  33. PatilSM ManuG ShivachandraJC Anil KumarKM VigneswaranJ RamuR Computational screening of benzophenone integrated derivatives (BIDs) targeting the NACHT domain of the potential target NLRP3 inflammasomeAdv Cancer Biol - Metastasis2022510005610.1016/j.adcanc.2022.100056
     [Google Scholar]
  34. KinraM. JosephA. NampoothiriM. AroraD. MudgalJ. Inhibition of NLRP3-inflammasome mediated IL-1β release by phenylpropanoic acid derivatives: In-silico and in-vitro approach.Eur. J. Pharm. Sci.202115710563710.1016/j.ejps.2020.10563733171231
     [Google Scholar]
  35. LiN. ZhangR. TangM. ZhaoM. JiangX. CaiX. YeN. SuK. PengJ. ZhangX. WuW. YeH. Recent progress and prospects of small molecules for NLRP3 inflammasome inhibition.J. Med. Chem.20236621144471447310.1021/acs.jmedchem.3c0137037879043
     [Google Scholar]
  36. BERNSTEIN FC. KOETZLETF. The protein data bank. A computer-based archival file for macromolecular structures.Eur J Biochem197780319324
     [Google Scholar]
  37. DekkerC. HinnigerA. Crystal structure of NLRP3 NACHT domain in complex with a potent inhibitor.J.Mol.Biol2021433167309167309
     [Google Scholar]
  38. GoddardT.D. HuangC.C. FerrinT.E. Software extensions to UCSF chimera for interactive visualization of large molecular assemblies.Structure200513347348210.1016/j.str.2005.01.00615766548
     [Google Scholar]
  39. VerdonkM.L. ColeJ.C. HartshornM.J. MurrayC.W. TaylorR.D. Improved protein–ligand docking using GOLD.Proteins200352460962310.1002/prot.1046512910460
     [Google Scholar]
  40. LillM.A. DanielsonM.L. Computer-aided drug design platform using PyMOL.J. Comput. Aided Mol. Des.2011251131910.1007/s10822‑010‑9395‑821053052
     [Google Scholar]
  41. CsizmadiaP. MarvinSketch and marvinview: Molecule applets for the world wide web.Proceedings of the 3rd International Electronic Conference on Synthetic Organic Chemistry, MDPI: Basel, Switzerland, 1–30 November 1999, pp. 1775.10.3390/ecsoc‑3‑01775
     [Google Scholar]
  42. OdaA. OkayasuM. KamiyamaY. YoshidaT. TakahashiO. MatsuzakiH. Evaluation of docking accuracy and investigations of roles of parameters and each term in scoring functions for protein–ligand docking using arguslab software.Bull. Chem. Soc. Jpn.200780101920192510.1246/bcsj.80.1920
     [Google Scholar]
  43. de BarrosW.A. NunesC.S. SouzaJ.A.C.R. NascimentoI.J.S. FigueiredoI.M. de AquinoT.M. VieiraL. FariasD. SantosJ.C.C. de FátimaÂ. The new psychoactive substances 25H-NBOMe and 25H-NBOH induce abnormal development in the zebrafish embryo and interact in the DNA major groove.Current Research in Toxicology2021238639810.1016/j.crtox.2021.11.00234888530
     [Google Scholar]
  44. BerendsenH.J.C. van der SpoelD. van DrunenR. GROMACS: A message-passing parallel molecular dynamics implementation.Comput. Phys. Commun.1995911-3435610.1016/0010‑4655(95)00042‑E
     [Google Scholar]
  45. ZoeteV. CuendetM.A. GrosdidierA. MichielinO. SwissParam: A fast force field generation tool for small organic molecules.J. Comput. Chem.201132112359236810.1002/jcc.2181621541964
     [Google Scholar]
  46. AlbinoS.L. da Silva MouraW.C. ReisM.M.L. SousaG.L.S. da SilvaP.R. de OliveiraM.G.C. BorgesT.K.S. AlbuquerqueL.F.F. de AlmeidaS.M.V. de LimaM.C.A. KuckelhausS.A.S. NascimentoI.J.S. JuniorF.J.B.M. da SilvaT.G. de MouraR.O. ACW-02 an acridine triazolidine derivative presents antileishmanial activity mediated by DNA interaction and immunomodulation.Pharmaceuticals202316220410.3390/ph1602020437259353
     [Google Scholar]
  47. Santos NascimentoI.J. AquinoT.M. Silva-JúniorE.F. Repurposing FDA-approved drugs targeting SARS-CoV2 3CL pro : A study by applying virtual screening, molecular dynamics, MM-PBSA calculations and covalent docking.Lett. Drug Des. Discov.202219763765310.2174/1570180819666220106110133
     [Google Scholar]
  48. José dos Santos NascimentoI. Mendonça de AquinoT. da Silva JúniorE.F. Olimpio de MouraR. Insights on microsomal prostaglandin E2 synthase 1 (mPGES-1) inhibitors using molecular dynamics and MM/PBSA calculations.Lett. Drug Des. Discov.20232010.2174/1570180820666230228105833
     [Google Scholar]
  49. dos Santos NascimentoI.J. de AquinoT.M. da Silva-JúniorE.F. Molecular docking and dynamics simulation studies of a dataset of NLRP3 inflammasome inhibitors.Recent Adv. Inflamm. Allergy Drug Discov.2022152808610.2174/2772270816666220126103909
     [Google Scholar]
  50. LaskowskiR.A. MacArthurM.W. MossD.S. ThorntonJ.M. PROCHECK: A program to check the stereochemical quality of protein structures.J. Appl. Cryst.199326228329110.1107/S0021889892009944
     [Google Scholar]
  51. WangQ. HeJ. WuD. WangJ. YanJ. LiH. Interaction of α-cyperone with human serum albumin: Determination of the binding site by using discovery studio and via spectroscopic methods.J. Lumin.2015164818510.1016/j.jlumin.2015.03.025
     [Google Scholar]
  52. GrantB.J. RodriguesA.P.C. ElSawyK.M. McCammonJ.A. CavesL.S.D. Bio3d: An R package for the comparative analysis of protein structures.Bioinformatics200622212695269610.1093/bioinformatics/btl46116940322
     [Google Scholar]
  53. ChaudhariA. ChaudhariM. MaheraS. SaiyedZ. NathaniN.M. ShuklaS. PatelD. PatelC. JoshiM. JoshiC.G. In-Silico analysis reveals lower transcription efficiency of C241T variant of SARS-CoV-2 with host replication factors MADP1 and hnRNP-1.Informatics in Medicine Unlocked20212510067010.1016/j.imu.2021.10067034307830
     [Google Scholar]
  54. KumariP. PoddarR. A comparative multivariate analysis of nitrilase enzymes: An ensemble based computational approach.Comput. Biol. Chem.20198310709510.1016/j.compbiolchem.2019.10709531442709
     [Google Scholar]
  55. KumariR. KumarR. LynnA. Open Source Drug Discovery Consortium g_mmpbsa--a GROMACS tool for high-throughput MM-PBSA calculations.J. Chem. Inf. Model.20145471951196210.1021/ci500020m24850022
     [Google Scholar]
  56. NascimentoI.J dos S. Molecular dynamics applied to discover antiviral agents.Frontiers in Computational Chemistry.Bentham Science202266213110.2174/9789815036848122060005
     [Google Scholar]
  57. NascimentoI.J.S. SantosM.B. MarinhoW.P.D.J. MouraR.O. Insights to design new drugs against human african trypanosomiasis targeting rhodesain using covalent docking, molecular dynamics simulations, and MM-PBSA calculations.Curr. Computeraided Drug Des.20242010.2174/011573409927479723120505582738310575
     [Google Scholar]
  58. KumariR. RathiR. PathakS.R. DalalV. Structural-based virtual screening and identification of novel potent antimicrobial compounds against YsxC of Staphylococcus aureus.J. Mol. Struct.2022125513247610.1016/j.molstruc.2022.132476
     [Google Scholar]
  59. KumariR. DalalV. Identification of potential inhibitors for LLM of Staphylococcus aureus : Structure-based pharmacophore modeling, molecular dynamics, and binding free energy studies.J. Biomol. Struct. Dyn.202240209833984710.1080/07391102.2021.193617934096457
     [Google Scholar]
  60. HeH. JiangH. ChenY. YeJ. WangA. WangC. LiuQ. LiangG. DengX. JiangW. ZhouR. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity.Nat. Commun.201891255010.1038/s41467‑018‑04947‑629959312
     [Google Scholar]
  61. El-SharkawyL.Y. BroughD. FreemanS. Inhibiting the NLRP3 inflammasome.Molecules20202523553310.3390/molecules2523553333255820
     [Google Scholar]
  62. JiangY. HeL. GreenJ. BlevinsH. GuoC. PatelS.H. HalquistM.S. McRaeM. VenitzJ. WangX.Y. ZhangS. Discovery of second-generation NLRP3 inflammasome inhibitors: Design, synthesis, and biological characterization.J. Med. Chem.201962219718973110.1021/acs.jmedchem.9b0115531626545
     [Google Scholar]
  63. LiH. GuanY. LiangB. DingP. HouX. WeiW. MaY. Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome.Eur. J. Pharmacol.202292817509110.1016/j.ejphar.2022.17509135714692
     [Google Scholar]
  64. McBrideC. TrzossL. PoveroD. LazicM. Ambrus-AikelinG. SantiniA. PranadinataR. BainG. StansfieldR. StaffordJ.A. VealJ. TakahashiR. LyJ. ChenS. LiuL. NespiM. BlakeR. KatewaA. KleinheinzT. Sujatha-BhaskarS. RamamoorthiN. SimsJ. McKenzieB. ChenM. UltschM. JohnsonM. MurrayJ. CiferriC. StabenS.T. TownsendM.J. StivalaC.E. Overcoming preclinical safety obstacles to discover ( S )- N -((1,2,3,5,6,7-Hexahydro- s -indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5 H -pyrazolo[5,1- b ][1,3]oxazine-3-sulfonamide (GDC-2394): A potent and selective NLRP3 inhibitor.J. Med. Chem.20226521147211473910.1021/acs.jmedchem.2c0125036279149
     [Google Scholar]
  65. DekkerC. MattesH. WrightM. BoettcherA. HinnigerA. HughesN. Kapps-FouthierS. EderJ. ErbelP. StieflN. MackayA. FaradyC.J. Crystal structure of NLRP3 NACHT domain with an inhibitor defines mechanism of inflammasome inhibition.J. Mol. Biol.20214332416730910.1016/j.jmb.2021.16730934687713
     [Google Scholar]
  66. ZhangX. XuA. RanY. WeiC. XieF. WuJ. Design, synthesis and biological evaluation of phenyl vinyl sulfone based NLRP3 inflammasome inhibitors.Bioorg. Chem.202212810601010.1016/j.bioorg.2022.10601035914391
     [Google Scholar]
  67. RiazM. RehmanA.U. ShahS.A. RafiqH. LuS. QiuY. WadoodA. Predicting multi-interfacial binding mechanisms of NLRP3 and ASC pyrin domains in inflammasome activation.ACS Chem. Neurosci.202112460361210.1021/acschemneuro.0c0051933504150
     [Google Scholar]
/content/journals/lddd/10.2174/0115701808303890240620074039
Loading
Molecular Dynamics Simulations and Binding Free Energy Calculations to Discover New Insights into NLRP3 Inhibitors
Letters in Drug Design & Discovery 21, 3839 (2024); https://doi.org/10.2174/0115701808303890240620074039
/content/journals/lddd/10.2174/0115701808303890240620074039
/content/journals/lddd/10.2174/0115701808303890240620074039
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): anti-inflammatory drugs; computer-aided drug design; inflammasome; Inflammation; molecular dynamics; NLRP3

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