Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64419210.2174/1573409919666230626140339ChemistryResearch ArticleVirtual Screening of Flavonoids against Plasmodium vivax Duffy Binding Protein Utilizing Molecular Docking and Molecular Dynamic SimulationYasirMuhammadinfo@benthamscience.netParkJinyounginfo@benthamscience.netHanEun-Taekinfo@benthamscience.netParkWon Suninfo@benthamscience.netHanJin-Heeinfo@benthamscience.netKwonYong-Sooinfo@benthamscience.netLeeHee-Jaeinfo@benthamscience.netChunWanjooinfo@benthamscience.netDepartment of Pharmacology, Kangwon National University School of MedicineDepartment of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of MedicineDepartment of Physiology, Kangwon National University School of MedicineCollege of Pharmacy, Kangwon National University School of Medicine0105202420561662707012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjeid.com/1573-4099/article/view/644192

Background:Plasmodium vivax (P. vivax) is one of the highly prevalent human malaria parasites. Due to the presence of extravascular reservoirs, P. vivax is extremely challenging to manage and eradicate. Traditionally, flavonoids have been widely used to combat various diseases. Recently, biflavonoids were discovered to be effective against Plasmodium falciparum.

Methods:In this study, in silico approaches were utilized to inhibit Duffy binding protein (DBP), responsible for Plasmodium invasion into red blood cells (RBC). The interaction of flavonoid molecules with the Duffy antigen receptor for chemokines (DARC) binding site of DBP was investigated using a molecular docking approach. Furthermore, molecular dynamic simulation studies were carried out to study the stability of top-docked complexes.

Results:The results showed the effectiveness of flavonoids, such as daidzein, genistein, kaempferol, and quercetin, in the DBP binding site. These flavonoids were found to bind in the active region of DBP. Furthermore, the stability of these four ligands was maintained throughout the 50 ns simulation, maintaining stable hydrogen bond formation with the active site residues of DBP.

Conclusion:The present study suggests that flavonoids might be good candidates and novel agents against DBP-mediated RBC invasion of P. vivax and can be further analyzed in in vitro studies.

FlavonoidsPlasmodium vivaxanti-malarial drugmolecular dockingmolecular dynamic simulationhydrogen bond.Tizifa, T.A.; Kabaghe, A.N.; McCann, R.S.; van den Berg, H.; van Vugt, M.; Phiri, K.S. Prevention efforts for malaria. Curr Trop Med Rep, 2018, 5(1), 41-50. doi: 10.1007/s40475-018-0133-ySutherland, C. J.; Tanomsing, N.; Nolder, D.; Oguike, M.; Jennison, C.; Pukrittayakamee, S.; Dolecek, C.; Hien, T. T.; Do Rosário, V.E.; Arez, A.P.J.T.J.o.i.d. Two nonrecombining sympatric forms of the human malaria parasite Plasmodium ovale occur globally. J. Infect. Dis., 2010, 201(10), 1544-1550.Ta, T.H.; Hisam, S.; Lanza, M.; Jiram, A.I.; Ismail, N.; Rubio, J.M.J.M.j. First case of a naturally acquired human infection with Plasmodium cynomolgi. Malar. J., 2014, 13(1), 1-7. doi: 10.1186/1475-2875-13-68Deane, L.M. Simian malaria in Brazil. Mem. Inst. Oswaldo Cruz, 1992, 87(S3), 1-20. doi: 10.1590/S0074-02761992000700001Brasil, P.; Zalis, M.G.; de Pina-Costa, A.; Siqueira, A.M.; Júnior, C.B.; Silva, S.; Areas, A.L.L.; Pelajo-Machado, M.; de Alvarenga, D.A.M.; da Silva Santelli, A.C.F.J.T.L.G.H. Outbreak of human malaria caused by plasmodium simium in the atlantic forest in rio de janeiro: A molecular epidemiological investigation. Lancet Glob. Health, 2017, 5(10), e1038-e1046. doi: 10.1016/S2214-109X(17)30333-9Lalremruata, A.; Magris, M.; Vivas-Martínez, S.; Koehler, M.; Esen, M.; Kempaiah, P.; Jeyaraj, S.; Perkins, D. J.; Mordmüller, B.; Metzger, W. G. J. E. Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon. EBioMedicine, 2015, 2(9), 1186-1192. doi: 10.1016/j.ebiom.2015.07.033Howes, R.E.; Battle, K.E.; Mendis, K.N.; Smith, D.L.; Cibulskis, R.E.; Baird, J.K.; Hay, S.I. Global epidemiology of Plasmodium vivax. Am. J. Trop. Med. Hyg., 2016, 95(S6), 15.Kar, S.; Sinha, A. Plasmodium vivax duffy binding protein-based vaccine: A distant dream. Front. Cell. Infect. Microbiol., 2022, 12, 916702. doi: 10.3389/fcimb.2022.916702Commons, R.J.; Simpson, J.A.; Thriemer, K.; Hossain, M.S.; Douglas, N.M.; Humphreys, G.S.; Sibley, C.H.; Guerin, P.J.; Price, R.N. Risk of plasmodium vivax parasitaemia after plasmodium falciparum infection: A systematic review and meta-analysis. Lancet Infect. Dis., 2019, 19(1), 91-101. doi: 10.1016/S1473-3099(18)30596-6 PMID: 30587297Adams, J.; Ntumngia, F.; Thomson-Luque, R.; Pires, C. The role of the human Duffy antigen receptor for chemokines in malaria susceptibility: Current opinions and future treatment prospects. J. Receptor Ligand Channel Res., 2016, 9, 1-11. doi: 10.2147/JRLCR.S99725 PMID: 28943755Chen, E.; Salinas, N.D.; Ntumngia, F.B.; Adams, J.H.; Tolia, N.H. Structural analysis of the synthetic Duffy Binding Protein (DBP) antigen DEKnull relevant for Plasmodium vivax malaria vaccine design. PLoS Negl. Trop. Dis., 2015, 9(3), e0003644.Karimi, A.; Majlesi, M.; Rafieian-Kopaei, M. Herbal versus synthetic drugs; beliefs and facts. J. Nephropharmacol., 2015, 4(1), 27-30. PMID: 28197471Havsteen, B.H.J.P. The biochemistry and medical significance of the flavonoids. Pharmacol. Ther., 2002, 96(2-3), 67-202.Nageen, B.; Sarfraz, I.; Rasul, A.; Hussain, G.; Rukhsar, F.; Irshad, S.; Riaz, A.; Selamoglu, Z.; Ali, M.J. Eupatilin: A natural pharmacologically active flavone compound with its wide range applications. J. Asian Nat. Prod. Res., 2020, 22(1), 1-16. doi: 10.1080/10286020.2018.1492565Ginwala, R.; Bhavsar, R.; Chigbu, D.G.I.; Jain, P.; Khan, Z.K. Potential role of flavonoids in treating chronic inflammatory diseases with a special focus on the anti-inflammatory activity of apigenin. Antioxidants, 2019, 8(2), 35.Messi, A.N.; Bonnet, S.L.; Owona, B.A.; Wilhelm, A.; Kamto, E.L.D.; Ndongo, J.T.; Siwe-Noundou, X.; Poka, M.; Demana, P.H.; Krause, R.W.J.P. In vitro and in silico potential inhibitory effects of new biflavonoids from ochna rhizomatosa on HIV-1 integrase and plasmodium falciparum. Pharmaceutics, 2022, 14(8), 1701. doi: 10.3390/pharmaceutics14081701Nasri, H. Cisplatin therapy and the problem of gender-related nephrotoxicity. J. Nephropharmacol., 2013, 2(2), 13-14.Studio, D. J. A. Discovery studio., 2008.Lovell, S.C.; Davis, I.W.; Arendall, W.B., III; De Bakker, P.I.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C.J.P.S. Structure validation by Calpha geometry: Phi,psi and Cbeta deviation. Proteins, 2003, 50(3), 437-450.Hassan, M.; Yasir, M.; Shahzadi, S.; Kloczkowski, A.J.A.O. Exploration of potential ewing sarcoma drugs from FDA-approved pharmaceuticals through computational drug repositioning, pharmacogenomics, molecular docking, and MD simulation studies. ACS Omega, 2022, 7(23), 19243-19260.Krishnamurthy, V.M.; Kaufman, G.K.; Urbach, A.R.; Gitlin, I.; Gudiksen, K.L.; Weibel, D.B.; Whitesides, G.M. Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding. Chem. Rev., 2008, 108(3), 946-1051. doi: 10.1021/cr050262p PMID: 18335973Batchelor, J.D.; Malpede, B.M.; Omattage, N.S.; DeKoster, G.T.; Henzler-Wildman, K.A.; Tolia, N.H. Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC. PLoS Pathog., 2014, 10(1), e1003869. doi: 10.1371/journal.ppat.1003869 PMID: 24415938Khan, M.T.H.; Orhan, I.; Şenol, F.S.; Kartal, M.; Şener, B.; Dvorská, M.; Šmejkal, K.; Šlapetová, T. Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies. Chem. Biol. Interact., 2009, 181(3), 383-389. doi: 10.1016/j.cbi.2009.06.024 PMID: 19596285Hassan, M.; Abbasi, M.A.; Aziz-ur-Rehman; Siddiqui, S.Z.; Hussain, G.; Shah, S.A.A.; Shahid, M.; Seo, S.Y. Exploration of synthetic multifunctional amides as new therapeutic agents for Alzheimer’s disease through enzyme inhibition, chemoinformatic properties, molecular docking and dynamic simulation insights. J. Theor. Biol., 2018, 458, 169-183. doi: 10.1016/j.jtbi.2018.09.018 PMID: 30243565Sharma, M.; Kohli, D.; Chaturvedi, S.; Sharma, S. Molecular modelling studies of some substitued 2-butylbenzimidazoles angiotensin ii receptor a ntagonists as antihypertensive agents. Dig. J. Nanomater. Biostructures, 2009, 4(4), 843-856.Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.Park, J.Y.; Lee, Y.; Lee, H.J.; Kwon, Y.S.; Chun, W. In silico screening of GABA aminotransferase inhibitors from the constituents of Valeriana officinalis by molecular docking and molecular dynamics simulation study. J. Mol. Model., 2020, 26(9), 228. doi: 10.1007/s00894-020-04495-1 PMID: 32780180Berendsen, H.J.; van der Spoel, D.; van Drunen, R. GROMACS: A message-passing parallel molecular dynamics implementation. Comput. Phys. Commun., 1995, 91(1–3), 43-56. doi: 10.1016/0010-4655(95)00042-EJo, S.; Kim, T.; Iyer, V.G. CHARMM‐GUI: A web‐based graphical user interface for CHARMM. J. Comput. Chem., 2008, 29(11), 1859-1865.Osii, R.S. Investigating the effect of Plasmodium falciparum infected red blood cells on dendritic cell function. PhD thesis, University of Glasgow, 2022.