• GERRY NUGRAHA Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
  • HARNO DWI PRANOWO Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
  • MUDASIR MUDASIR Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
  • ENADE PERDANA ISTYASTONO Faculty of Pharmacy, Universitas Sanata Dharma, Yogyakarta 55281, Indonesia.



histamine H4, seliforant, SBVS, homology modeling, molecular docking, molecular dynamics


Objective: This study aimed to construct a virtual target to be used in structure-based virtual screening (SBVS) campaigns to discover ligands for human histamine receptor H4 (hHRH4).

Methods: The virtual targets construction was initiated by hHRH4 homology modeling, followed by molecular docking of seliforant to the homolog model, and the virtual target candidate was constructed. The hHRH4 complexed to seliforant was subjected to molecular dynamics (MD) simulations in 100 ns. Finally, the pose with the least free energy of binding from the MD simulations was selected for further validation through re-docking simulations. All simulations were conducted by using the YASARA-Structure program package.

Results: This study resulted in one validated target for SBVS protocols development. All RMSD values in the internal validation in snapshot 519 molecular dynamics simulation results were less than 2 Å, and this hHRH4 homology model is valid as a virtual target in an SBVS protocol. Moreover, using the clusterization module on MD simulations analysis, ten different virtual targets were available for further utilization.


Conclusion: Virtual targets resulted from this study offer more possibilities to construct SBVS protocols to identify hHRH4 ligands. The validated virtual target and the ten different virtual targets resulted from clusterization can be accessed in the following GitHub repository:


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Tiligada E, Zampeli E, Sander K, Stark H, Tiligada E, Zampeli E, Sander K, Stark H. Histamine H 3 and H 4 receptors as novel drug targets Histamine H 3 and H 4 receptors as novel drug targets. Expert Opin Investig Drugs. 2009;18(10):1–15.

Gutzmer R, Gschwandtner M, Rossbach K, Mommert S, Werfel T, Kietzmann M, Baeumer W. pathogenetic and therapeutic implications of the histamine H4 receptor in inflammatory skin diseases and pruritus. Front Biosci - Sch. 2011 Jan 6;1–10.

Glatzer F, Gschwandtner M, Ehling S, Rossbach K, Janik K, Wolfgang B, Kietzmann M, Werfel T, Klos A, Gutzmer R. histamine induces proliferation in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor. Am Acad Allergy, Asthma Immunol. 2013;132(6):1–10.

Deiteren A, De Man JG, Pelckmans PA, De Winter BY. histamine H4 receptors in the gastrointestinal tract. Br J Pharmacol. 2015;172(5):1–14.

Saravanan C, K. Bharti S, Jaggi S, K. Singh S. histamine h4 receptor: a novel target for inflammation therapy. Mini-Reviews Med Chem. 2011;11(2):1–16.

Balbino AM, Lima LJS, Fernandes GAB, Corrêa MF, Gomes E, Landgraf MA, Fernandes JPS, Landgraf RG. The novel H4R antagonist 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-Yl)methyl]-4-methyl-piperazine (LINS01007) attenuates several symptoms in murine allergic asthma. Cell Physiol Biochem. 2020;54(6):1163–76.

Watanabe M, Kobayashi T, Ito Y, Fukuda H, Yamada S. design and synthesis of histamine H3 / H4 receptor ligands with a cyclopropane scaffold. Bioorg Med Chem Lett [Internet]. 2018;28:1–4. Available from:

Stasiak A, Gola J, Kraszewska K, Mussur M, Kobos J, Mazurek U, Stark H, Fogel WA. experimental autoimmune myocarditis in rats and therapeutic histamine H1 – H4 receptor inhibition. J Physiol Pharmacol. 2018;69(6):1–12.

Neumann D. role of the histamine H4-receptor in bronchial asthma. In: Handbook of Experimental Pharmacology. Switzerland: Springer International Publishing; 2016. p. 1–13.

Zhou P, Homberg JR, Fang Q, Wang J, Li W, Meng X, Shen J, Luan Y, Liao P, Swaab DF, Shan L, Liu C. histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model. Brain Behav Immun [Internet]. 2019;76:1–13. Available from:

Shan Y, Gao Y, Zhang L, Ma L, Shi Y, Liu X. H4 receptor inhibits lipopolysaccharide-induced nf-κb activation by interacting with tumor necrosis factor receptor-associated factor 6. Neuroscience [Internet]. 2019;398:1–13. Available from:

Guillot-Sestier MV, Doty KR, Town T. innate immunity fights alzheimer’s disease. Trends Neurosci [Internet]. 2015;38(11):1–8. Available from:

Nicoud MB, Táquez Delgado MA, Sarasola M de la P, Vidal A, Speisky D, Cremaschi GA, Sterle HA, Medina VA. Impact of histamine H4 receptor deficiency on the modulation of T cells in a murine breast cancer model. Cancer Immunol Immunother [Internet]. 2021;70(1):233–44. Available from:

Strakhova MI, Nikkel AL, Manelli AM, Hsieh GC, Esbenshade TA, Brioni JD, Bitner RS, Road AP, Park A. localization of histamine H 4 receptors in the central nervous system of human and rat. Brain Res [Internet]. 2009;1250(847):1–8. Available from:

Sterle HA, Nicoud MB, Massari NA, Táquez Delgado MA, Herrero Ducloux M V., Cremaschi GA, Medina VA. immunomodulatory role of histamine H4 receptor in breast cancer. Br J Cancer. 2018 Jan 8;120(1):1–11.

Kumar A, Pasam VR, Thakur RK, Singh M, Singh K, Shukla M, Yadav A, Dogra S, Sona C, Umrao D, Jaiswal S, Ahmad H, Rashid M, Singh SK, Wahajuddin M, Dwivedi AK, Siddiqi MI, Lal J, Tripathi RP, Yadav PN. novel tetrahydroquinazolinamines as selective histamine 3 receptor antagonists for the treatment of obesity. J Med Chem. 2019 May 9;62(9):1–18.

Dyhrfjeld-Johnsen J, Attali P. management of peripheral vertigo with antihistamines: new options on the horizon. Br J Clin Pharmacol. 2019;85(10):2255–63.

Venail F, Attali P, Wersinger E, Gomeni R, Poli S, Schmerber S. safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modelling of the novel H4 receptor inhibitor SENS-111 using a modified caloric test in healthy subjects. Br J Clin Pharmacol. 2018;84(12):1–24.

Petremann M, Gueguen C, Delgado Betancourt V, Wersinger E, Dyhrfjeld‐Johnsen J. effect of the novel histamine H 4 receptor antagonist SENS‐111 on spontaneous nystagmus in a rat model of acute unilateral vestibular loss. Br J Pharmacol. 2019;1–11.

Schirmer B, Neumann D. The function of the histamine h4 receptor in inflammatory and inflammation-associated diseases of the gut. Int J Mol Sci. 2021;22(11).

Nugraha G, Istyastono EP. Virtual target construction for structure-based screening in the discovery of histamine h2 receptor ligands. Int J Appl Pharm. 2021;13(3):1–3.

Cavasotto CN, Orry AJW. ligand docking and virtual screening in structure-based drug discovery. Curr Top Med Chem. 2007;7:1006–14.

Hinchliffe A. molecular modelling for beginners. Second. Weinheim, Germany: John Wiley & Sons Ltd; 2008. 1–407 p.

Tan L, Geppert H, Sisay MT, Gütschow M, Bajorath J. integrating structure- and ligand-based virtual screening: Comparison of individual, parallel, and fused molecular docking and similarity search calculations on multiple targets. ChemMedChem. 2008;3(10):1–6.

Leach AR, Shoichet BK, Peishoff CE. docking and scoring. Am Chem Soc. 2006;49(20):1–5.

Kroemer RT. structure-based drug design: docking and scoring. Curr Protein Pept Sci. 2007;8:1–18.

Vyas VK, Ukawala RD, Ghate M, Chintha C. homology modeling a fast tool for drug discovery: current perspectives. Indian J Pharm Sci [Internet]. 2012;1(1):1–17. Available from:

Krieger E, Koraimann G, Vriend G. increasing the precision of comparative models with YASARA NOVA -a self-parameterizing force field. Proteins Struct Funct Genet. 2002;47(3):1–10.

Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S. structure of the human histamine H1 receptor complex with doxepin. Nature [Internet]. 2011;475(7354):1–8. Available from:

Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S. Structure of the human histamine H1 receptor in complex with doxepin [Internet]. RSCB PDB. 2011 [cited 2019 Aug 15]. Available from:

Wishart D, Feunang Y, Guo A, Lo E, Marcu A, Grant J, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. seliforant [Internet]. DrugBank 5.0. 2018 [cited 2019 Aug 15]. Available from:

The UniProt Consortium. Histamine H4 receptor [Internet]. Nucleic Acids Research. 2019 [cited 2019 Oct 17]. p. 1–10. Available from:

Nugraha G. github [Internet]. 2021 [cited 2021 Nov 23]. p. 1. Available from:

Land H, Humble MS. YASARA: a tool to obtain structural guidance in biocatalytic investigations. In: Methods in Molecular Biology. 2018. p. 43–66.

Cortés-Benítez F, Roy J, Perreault M, Maltais R, Poirier D. 16-picolyl-androsterone derivative exhibits potent 17β-HSD3 inhibitory activity, improved metabolic stability and cytotoxic effect on various cancer cells: Synthesis, homology modeling and docking studies. J Steroid Biochem Mol Biol. 2021;210(October 2020):1–13.

Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, Monsma FJ. molecular modeling and site-specific mutagenesis of the histamine-binding site of the histamine H4 receptor. Mol Pharmacol. 2002;62(1):1–10.

Lengauer T, Rarey M. computational methods for biomolecular docking. Curr Opin Struct Biol. 1996;6(3):1–5.

Nurhidayah M, Fadilah F, Arsianti A, Bahtiar A. Identification of FGFR inhibitor as ST2 receptor/interleukin-1 receptor-like 1 inhibitor in chronic obstructive pulmonary disease due to exposure to e-cigarettes by network pharmacology and molecular docking prediction. Int J Appl Pharm. 2022;14(2):10.

Liu K, Watanabe E, Kokubo H. exploring the stability of ligand binding modes to proteins by molecular dynamics simulations. J Comput Aided Mol Des. 2017;31(2):1–10.

Marcou G, Rognan D. optimizing fragment and scaffold docking by use of molecular interaction fingerprints. J Chem Inf Model. 2007;47(1):1–13.

Schneider G. de novo molecular design. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co.; 2014. 1–578 p.

Istyastono EP. construction, validation and application of structure‐based virtual screening protocols to discover new cyclooxygenase‐2 inhibitors. Indo J Chem. 2012;12(2):1–5.



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