Computational approach to determine the combination of polyherbs based on the interaction of their metal complexes on the mucoadhesive properties of type II mucin

Eka Diyah Putri Lestari Sri Widyarti Djoko Herry Santjojo Nashi Widodo Sutiman Bambang Sumitro   

Open Access   

Published:  Apr 05, 2023

DOI: 10.7324/JAPS.2023.35062

Mucin is the main mucus component besides water, which comes from the glycoprotein group. Mucoadhesive properties can be analyzed based on the binding interactions between compounds and mucin in mucus. This research is an in-silico approach aiming to obtain bioactive compounds that have a stable interaction with mucin-type II (MUC2) by screening ten compounds used in Indonesian herbal medicines. Molecular docking was used as a procedure for forming the compound-mucin complexes. Furthermore, molecular dynamic simulation with YASARA Dynamics software was used to obtain the stability of compound-mucin complexes. The curcumin-metal ions and kaempferol-metal ions complexes showed the most stable binding affinity and interaction with MUC2 compared to eight other ligands. Based on the molecular dynamic simulation, kaempferol-metal ions complexes are predicted to interact in the D3 chain, while curcumin-metal ions complexes more stably interact with the CysD1 chain. Both complex interactions simultaneously strengthen and synergize interactions with MUC2. Herbs containing one or both bioactive compounds, curcumin, and kaempferol are supposed to be composed into a polyherbal composition to obtain optimal mucoadhesive properties for MUC2.

Keyword:     Molecular dynamic mucoadhesive MUC2 medicinal herbs


Lestari EDP, Widyarti S, Santjojo DH, Widodo N, Sumitro SB. Computational approach to determine the combination of polyherbs based on the interaction of their metal complexes on the mucoadhesive properties of type II mucin. J Appl Pharm Sci, 2023.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Aggett PJ Harries JT. Current status of zinc in health and disease states. Arch Dis Childh, 1979; 54(12):909.

Agoro R, Mura C. Inflammation-induced up-regulation of hepcidin and down-regulation of ferroportin transcription are dependent on macrophage polarization. BCMD, 2016; 61:16-25.

Ahmadinejad F, Geir Møller S, Hashemzadeh-Chaleshtori M, Bidkhori G, Jami MS. Molecular mechanisms behind free radical scavengers function against oxidative stress. Antioxidants, 2017; 6(3):51.

Alexander J, Kowdley KV. HFE-associated hereditary hemochromatosis. Genet Med, 2009; 11(5):307-13.

Ali MS, Pearson JP. Upper airway musin gene expression: a review. Laryngoscope, 2007; 117(5):932-8.

Andreini C, Banci L, Bertini I, Elmi S, Rosato A. Non-heme iron through the three domains of life. Proteins, 2007; 67(2):317-24.

Andreini C, Banci L, Bertini I, Rosato A. Occurrence of copper proteins through the three domains of life: a bioinformatic approach. J Proteome Res, 2008; 7(01):209-16.

Aristyani S, Widyarti S, Sumitro, SB. Network analysis of indigenous Indonesia medical plants for treating tuberculosis. Pharmacogn J, 2018; 10(6):1159-64.

Balabushevich NG, Kovalenko EA, Mikhalchik EV, Filatova LY, Volodkin D, Vikulina AS. Mucin adsorption on vaterite CaCO3 microcrystals for the prediction of mucoadhesive properties. J Colloid Interface Sci, 2019; 545:330-9.

Banerjee P, Dehnbostel FO, Preissner R. Prediction is a balancing act: importance of sampling methods to balance sensitivity and specificity of predictive models based on imbalanced chemical data sets. Front. Chem, 2018a; 362.

Banerjee P, Eckert OA, Schrey AK, Preissner R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res, 2018b; 46(W1):W257-63.

Bencini A, Failli P, Valtancoli B, Bani D. Low molecular weight compounds with transition metals as free radical scavengers and novel therapeutic agents. Cardiovasc Hematol Agents Med Chem, 2010; 8(3):128-46.

Biovia. Dassault Systèmes, Discovery studio visualizer, V21.1.0.20298. Dassault Systèmes, San Diego, CA, 2020.

Brandt M, Schramm VL. Mammalian manganese metabolism and manganese uptake and distribution in rat hepatocytes. Manganese in metabolism and enzyme function, 1986; 50:3-16.

Capo CR, Pedersen JZ, Falconi M, Rossi L. Oleuropein shows copper complexing properties and noxious effect on cultured SH-SY5Y neuroblastoma cells depending on cell copper content. J Trace Elem in Med Biol, 2017; 44:225-32.

Coates J. Interpretation of infrared spectra, a practical approach. Encyclopedia Anal Chem, 2000; 12:10815-37.

Cojocaru C, Clima L. Binding assessment of methylene blue to human serum albumin and poly (acrylic acid): experimental and computer-aided modeling studies. J Molecular Liquids, 2019; 285:811-21.

Corfield P. The interaction of the gut microbiota with the mucus barrier in health and disease in human. Microorganisms, 2018; 6(3): 78- 135.

Cox DW. Disorders of copper transport. Br Med Bull, 1999; 55(3):544-55.

Dash R, Das R, Junaid M, Akash MFC, Islam A, Hosen SZ. In silico-based vaccine design against Ebola virus glycoprotein. AABC, 2017; 10:11-28.

Devi KP, Malar DS, Nabavi SF, Sureda A, Xiao J, Nabavi SM, Daglia M. Kaempferol and inflammation: from chemistry to medicine. Pharmacol Res, 2015; 99:1-10.

Dong J, Wang NN, Yao ZJ, Zhang L, Cheng Y, Ouyang D, Lu A, Cao D. ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database. J Cheminform, 2018; 10:29.

Dougherty DA. The cation-π interaction. Acc Chem Res, 2013; 46(4):885-93.

Drwal MN, Banerjee P, Dunkel M, Wettig MR, Preissner R. ProTox: a web server for the insilico prediction of rodent oral toxicity. Nucleic Acids Res, 2014; 42(W1):W53-8.

Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R and Lee T. A point-charge force field for molecular mechanics simulations of proteins. J Comput Chem, 2003; 24:1999-2012.

Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock Vina 1.2.0: new docking methods, expanded force field, and python bindings. J Chem Inf Model, 2021; 61(8):3891-8.

Engwa GA. Free radicals and the role of plant phytochemicals as antioxidants against oxidative stress-related diseases. Phytochemicals: source of antioxidants and role in disease prevention. BoD-Books on Demand, 2018; 7:49-74.

Fatimah C, Rosidah HU, Suryanto D. Anti-tuberculosis assay of nanoherbal and ethanolic extract of Lantana camara Linn flos in vitro and in vivo. IIOABJ, 2017; 8(2):92-7.

Ferreira CR, Gahl WA. Disorders of metal metabolism. Transl Sci Rare Dis, 2017; 2(3-4):101-39.

Filimonov D, Poroikov V. Probabilistic approaches in activity prediction Royal Society of Chemistry, Cambridge, UK, pp. 182-216, 2008.

Gupta SP. Roles of metals in human health. MOJ Bioorg Org Chem, 2018; 2(5):221-4.

Hadacek F, Bachmann G. Low-molecular-weight metabolite systems chemistry. Front Environment Sci, 2015; 3:1-2.

Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform, 2012; 4(1):1-7.

Jabeen E, Janjua NK, Ahmed S, Murtaza I, Ali T, Hameed S. Radical scavenging propensity of Cu2+, Fe3+ complexes of flavonoids and in-vivo radical scavenging by Fe3+-primuletin. Spectrochim Acta Part A Mol biomol spectr, 2017; 171:432-8.

Jadid N, Kurniawan E, Himayani CES, Prasetyowati I, Purwani KI, Muslihatin W, Hidayati D, Tjahjaningrum ITD. An ethnobotanical study of medicinal plants used by the Tengger tribe in Ngadisari village, Indonesia. PLos One, 2020; 15(7):e0235886.

Javitt G, Khmelnitsky L, Albert L, Bigman LS, Elad N, Morgenstern D, Ilani T, Levy Y, Diskin R, Fass D. Assembly mechanism of mucin and von willebrand factor polymers. Cell, 2020; 183(3):717-29.

Jayaram B, Singh T, Mukherjee G, Mathur A, Shekhar S, Shekhar V. Sanjeevini: a freely accessible web-server for target directed lead molecule discovery. BMC Bioinformat. BioMed Central, 2012; 13(17):1-3.

Johansson MEV, Sjövall H, Hansson GC. The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. Hepatol, 2013; 10(6):352-61.

Jomova K, Makova M, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Rhodes CJ, Valko M. Essential metals in health and disease. Chem Biol Interactions, 2022; 22:110173.

Kaim W, Schwederski B, Klein A. Bioinorganic chemistry: inorganic elements in the chemistry of life-an introduction and guide. 2nd edition, John Wiley & Sons, New York, NY, 2013.

Khairullah AR, Solikhah TI, Ansori ANM, Fadholly A, Ram SC, Ansharieta R, Anshori A. A review of an important medicinal plant: alpinia galanga (L.) willd. Syst Rev Pharm, 2020; 11(10):387-95.

Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH. PubChem: substance and compound databases. Nucleic Acids Res, 2016; 44(D1):D1202-13.

Krieger E, Koraimann G, Vriend G. Increasing the precision of comparative models with YASARA NOVA-a self-parameterizing force field. Proteins, 2002; 47(3):393-402.

Krieger E, Nielsen JE, Spronk CAEM, Vriend G. Fast empirical pKa prediction by Ewald summation. J Molecular Graph Mod, 2006; 25(4):481-6.

Krieger E, Vriend G. New ways to boost molecular dynamics simulations. J Comput Chem, 2015; 36(13):996-1007.

Kristianto S, Widyarti S, Santjojo DJ, Sumitro SB. Identification and characterization of Shogaol And 6-Gingerol complex from Madurese Herbal medicine. Egypt J Chem, 2022; 65(3):1-2.

Lagunin A, Filimonov D, Poroikov V. Multi-targeted natural products evaluation based on biological activity prediction with PASS. Curr Pharm Des, 2010; 16(15):1703-17.

Lai SK, Wang YY, Wirtz D, Hanes J. Micro- and macrorheology of mucus. Advanced Drug Delivery Reviews, 2009; 61(2):86-100.

Liao D, Fan Q, Bao L. The role of superoxide dismutase in the survival of mycobacterium tuberculosis in Macrophages. Jpn J Infect Dis, 2013; 66(6):480-8.

Linden SK, Sutton P, Karlsson NG, Korolik V, McGuckin MA. Musins in the mucosal barrier to infection. Mucosal Immunol, 2008; 1(3):183-97.

Ling KH. 2009. Guide to medicinal plants: an illustrated scientific and medicinal approach. World Scientific, Singapore.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ, An Experimental and computational approach to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev, 1997; 23:3-25.

Liu X, Shi D, Zhou S, Liu H, Liu H, Yao X. Molecular dynamics simulations and novel drug discovery. Expert Opin Drug Discov, 2018; 13(1):23-37.

Lobanov MY, Bogatyreva NS, Galzitskaya OV. Radius of gyration as an indicator of protein structure compactness. Molecular Biology, 2008; 42(4):623-8.

Lu W, Zheng J. The function of musins in the COPD airway. Curr Respirator Care Rep, 2013; 2(3):155-66.

Macielag MJ. Chemical properties of antimicrobials and their uniqueness. Antibiot Discov Devel, 2011; 1:793-820.

Menchicchi B, Fuenzalida JP, Hensel A, Swamy MJ, David L, Rochas C, Goycoole FM. Biophysical analysis of the molecular interactions between polysaccharides and mucin. Biomacromolecules, 2015; 16(3):924- 35.

Mitra R, Orbell J, Muralitharan MS. Agriculture - medicinal plants of Malaysia. Asia Pac. Biotech. News, 2007; 11:105-10.

Montano MCJ, Burgos-Morón E, Pérez-Guerrero C, López- Lázaro M. A review on the dietary flavonoid kaempferol. Mini Rev Med Chem, 2011; 11(4):298-344.

Nazar S, Ravikumar S, Williams GP. Ethnopharmacological survey of medicinal plants along the Southwest coast of India. J. Herbs, Spices, Med. Plants, 2008; 14(3-4):219-39.

O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Chem, 2011; 3(1):1-4.

O'Brien RJ, Nunn PP. The need for new drugs against tuberculosis. Obstacles, opportunities, and next steps. Am J Respir Crit Care Med, 2001; 163(5):1055-8.

Odhar HA, Ahjel SW, Odhar ZA. Computational screening of FDA approved drugs from ZINC database for potential inhibitors of Zika Virus NS2B/NS3 protease: a molecular docking and dynamics simulation study. J Pharm Res Int, 2021; 33(39B):308-19.

Ortiz AO, Torres LM, Moyado JAV, Peña EAP, López JLB, Bernad MJ, Carvalho JCT, Navarrete A. Mucoadhesive efect of Curcuma longa extract and curcumin decreases the ranitidine efect, but not bismuth subsalicylate on ethanol-induced ulcer model. Sci Rep, 2019; 9:16622.

Pal S. Fundamentals of molecular structural biology. Chapter 4: chemical basis of biology. Academic Press, New York, NY, pp61-82, 2020.

Panteva MT, Giambasu GM, York DM. Force field for Mg2+, Mn2+, Zn2+, and Cd2+ ions that have balanced interactions with nucleic acids. J Phys Chem B, 2015; 119(50):15460-70.

Pollastri MP. Overview on the rule of five. Curr Protocol Pharmacol, 2010; 49(1):9-12.

Purba EC, Silalahi M, Nisyawati N. Gastronomic ethnobiology of "terites"-a traditional Batak Karo medicinal food: a ruminant's stomach content as a human food resource. J. Ethn. Foods, 2018; 5(2):114-20.

Puspitarini S, Widodo N, Widyarti S, Jatmiko YD, Rifa'i M. Polyherbal effect between Phyllanthus urinaria and Curcuma longa as an Anticancer and Antioxidant. RJPT, 2022; 15(2):671-8.

Rubin BK. Mucus and musins. Otolaryngol Clin North Am, 2010; 43(1):27-34.

Schaeffer L. 2008. The role of functional groups in drug- receptor interactions. In: the practice of medicinal chemistry. New York: Academic Press 464-80.

Schottel BL, Chifotides HT, Dunbar KR. Anion-π interactions. Chem Soc Rev, 2008; 37(1):68-83.

Schrödinger L, DeLano W. PyMOL. 2020. Available via http://

Sgrignani J, Chen J, Alimonti A, Cavalli A. How phosphorylation influences E1 subunit pyruvate dehydrogenase: a computational study. Sci Rep, 2018;8(1):1-1.

Silalahi M, Walujo EB, Supriatna J, Mangunwardoyo W. The local knowledge of medicinal plants trader and diversity of medicinal plants in the Kabanjahe traditional market, North Sumatra, Indonesia. J Ethnopharmacol, 2015; 175:432-43.

Silverman RB. The organic chemistry of drug design and drug action. Chapter 3: receptors. 2nd edition, Academic Press, New York, NY, pp 121-72l, 2004.

Smart JD. The basics and underlying mechanisms of mucoadhesion. Adv Drug Deliv Rev, 2005; 57(11):1556-68.

Smith MD, Rao S, Segelken E, Cruz L. Force-field induced bias in the structure of Aβ21−30: a comparison of OPLS, AMBER, CHARMM, and GROMOS force fields. J Chem Inf Model, 2015; 55:2587−95.

Sukenti K, Hakim L, Indriyani S, Purwanto Y, Matthews PJ. Ethnobotanical study on local cuisine of the Sasak tribe in Lombok Island, Indonesia. J Ethn Foods, 2016; 3:189-200.

Sukmaningsih AASA, Permana S, Santjojo DJDH, Wardoyo AYP, Sumitro SB. Investigating natural transition metal coordination anthocyanin complex in java plum (Syzygium cumini) fruit as free radical scavenging. RASAYAN J Chem, 2018; 11(3):1193-03.

Sumitro SB, Sukmaningsih A. Herbal medicine, radical scavenger and metal detoxification: bioinorganic, complexity and nano science perspectives. IOP Conf Ser Earth Environ Sci, 2018; 130:012003.

Szent-Györgyi A. Introduction to a submolecular biology. Academic Press, New York, NY, 1960.

Szent-Györgyi A. Bioelectrics. Academic Press, New York, NY, 1968.

Techaprasan J, Klinbunga S, Ngamriabsakul C, Jenjittikul T. Genetic variation of Kaempferia (Zingiberaceae) in Thailand based on chloroplast DNA (psbA-trnH and petA-psbJ) sequences. Genet. Mol. Res. 2010; 9:1957-73.

Trott O, Olson AJ. Autodock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem, 2010; 31:455-61.

Tuschl K, Mills PB, Clayton PT. Manganese and the brain, Int Rev Neurobiol. 2013; 110:277-312.

Umar MI, Bin Asmawi MZ, Sadikun A, Altaf R, Iqbal MA. Phytochemistry and medicinal properties of Kaempferia galanga L. (Zingiberaceae) extracts. Afr J Pharm Pharmacol, 2011; 5(14):1638-47.

US Department of Agriculture, Agricultural Research Service. 1992-2016. Dr. Duke's phytochemical and ethnobotanical databases. Available via (Accessed 13 May 2021).

Vareille M, Kieninger E, Edwards MR, Regamey N. The airway epithelium: soldier in the fight against respiratory viruses. Clin Microbiol Rev, 2011; 24(1):210-29.

Vulpe CD, Packman S. Cellular copper transport. Ann Rev Nutr, 1995; 15(1):293-22.

Wagner CE, Wheeler KM, Ribbeck K. Mucins and their role in shaping the functions of mucus barriers. Annu Rev Cell Dev Biol, 2018; (34):189-215.

Widodo WT, Santjojo DJDH, Widyarti S, Sumitro SB. Exploring and proving complex compounds in brotowali (Tinospora crispa). RASAYAN J. Chem, 2021; 14(4):2666-70.

Widyarti S, Kamaruddin M, Aristyani S, Elvina M, Subagjo S, Rahayu T, Sumitro SB. Bioinorganic chemistry and computational study of herbal medicine to treatment of tuberculosis. Intechopen, 2019; 1(1):e90155.

Wijayakusuma H. Ramuan lengkap herbal taklukkan penyakit. Pustaka Bunda Depok, Depok, Indonesia, 2008.

Xiong G, Wu Z, Yi J, Fu L, Yang Z, Hsieh C, Yin M, Zeng X, Wu C, Chen X, Hou T, Cao D. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res, 2021; 49:W5-14.

Yamamoto E, Akimoto T, Mitsutake A, Metzler R. Universal relation between instantaneous diffusivity and radius of gyration of proteins in aqueous solution. Phys Rev Lett, 2021; 126(12):128101.

Yang X, Forier K, Steukers L, Vlierberghe SV, Dubrue P, Braeckmans K, Glorieux S, Nauwynck HJ. Immobilization of pseudorabies virus in porcine tracheal respiratory mucus revealed by single particle tracking. PLoS One, 2012; 7(12):e51054.

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