VIRTUAL TARGET CONSTRUCTION FOR DISCOVERY OF HUMAN HISTAMINE H4 RECEPTOR LIGANDS EMPLOYING A STRUCTURE-BASED VIRTUAL SCREENING APPROACH

GERRY NUGRAHA; HARNO DWI PRANOWO; MUDASIR MUDASIR; ENADE PERDANA ISTYASTONO

doi:10.22159/ijap.2022v14i4.44067

Authors

GERRY NUGRAHA Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia, Pharmacy, STIKES ‘Aisyiyah, Palembang 30961, Indonesia https://orcid.org/0000-0001-7879-5630
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, 4Department 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

DOI:

https://doi.org/10.22159/ijap.2022v14i4.44067

Keywords:

Histamine H4, Seliforant, SBVS, Homology modeling, Molecular docking, Molecular dynamics

Abstract

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: https://github.com/nugrahagerry/hHRH4.

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References

Tiligada E, Zampeli E, Sander K, Stark H, Tiligada E, Zampeli E, Sander K, Stark H. Histamine H3 and H4 receptors as novel drug targets histamine H3 and H4 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 (Schol Ed). 2011;3(3):985-94. doi: 10.2741/203. PMID 21622248.

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, Bharti KS, Jaggi S, K Singh S. histamine H4 receptor: a novel target for inflammation therapy. Mini Rev Med Chem. 2011;11(2):1-16.

Balbino AM, Lima LJS, Fernandes GAB, Correa 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. doi: 10.33594/000000307, PMID 33216475.

Kawatani M, Kamiya M, Takahashi H, Urano Y. Factors affecting the uncaging efficiency of 500 nm light-activatable BODIPY caging group. Bioorg Med Chem Lett. 2018;28(1):1-5. doi: 10.1016/j.bmcl.2017.11.030.

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. doi: 10.26402/ jpp.2018.6.13, PMID 30898985.

Neumann D. Role of the histamine H4-receptor in bronchial asthma. H and b Exp Pharmacol. 2016:1-13.

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. 2019;76:61-73. doi: 10.1016/j.bbi.2018.11.006. PMID 30408497.

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. 2019;398:113-25. doi: 10.1016/ j.neuroscience.2018.11.050. PMID 30528857.

Guillot Sestier MV, Doty KR, Town T. Innate immunity fights alzheimer’s disease. Trends Neurosci. 2015;38(11):674-81. doi: 10.1016/j.tins.2015.08.008. PMID 26549882.

Nicoud MB, Taquez Delgado MA, de la Sarasola MP, 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. 2021;70(1):233–44. doi: 10.1007/s00262-020-02672-y.

Strakhova MI, Nikkel AL, Manelli AM, Hsieh GC, Esbenshade TA, Brioni JD, Bitner RS, Road AP, Park A. localization of histamine H4 receptors in the central nervous system of human and rat. Brain Res. 2009;1250;847:1-8. doi: 10.1016/j.brainres.2008.11.018.

Sterle HA, Nicoud MB, Massari NA, Taquez Delgado MA, Herrero Ducloux MV, Cremaschi GA, Medina VA. Immunomodulatory role of histamine H4 receptor in breast cancer. Br J Cancer. 2019;120(1):128-38. doi: 10.1038/s41416-018-0173-z, PMID 29988113.

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):4638-55. doi: 10.1021/acs.jmedchem.9b00241, PMID 30998358.

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. doi: 10.1111/bcp.14046, PMID 31269270.

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):2836-48. doi: 10.1111/bcp.13744, PMID 30152527.

Petremann M, Gueguen C, Delgado Betancourt V, Wersinger E, Dyhrfjeld-Johnsen J. Effect of the novel histamine H4 receptor antagonist SENS-111 on spontaneous nystagmus in a rat model of acute unilateral vestibular loss. Br J Pharmacol. 2020;177(3):623-33. doi: 10.1111/bph.14803. PMID 31347148.

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). doi: 10.3390/ijms22116116, PMID 34204101.

Nugraha G, Istyastono EP. Virtual target construction for structure-based screening in the discovery of histamine H2 receptor ligands. Int J App Pharm. 2021;13(3):239-41. doi: 10.22159/ijap.2021v13i3.41202.

Cavasotto CN, Orry AJW. Ligand docking and structure-based virtual screening in drug discovery. Curr Top Med Chem. 2007;7(10):1006-14. doi: 10.2174/156802607780906753, PMID 17508934.

Hinchliffe A. Molecular modelling for beginners. Second. Chichester: John Wiley & Sons Ltd; 2008. p. 1-407.

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. Chem Med Chem. 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(4):312-28. doi: 10.2174/138920307781369382, PMID 17696866.

Vyas VK, Ukawala RD, Ghate M, Chintha C. Homology modeling a fast tool for drug discovery: current perspectives. Indian J Pharm Sci. 2012;74(1):1-17. doi: 10.4103/0250-474X.102537, PMID 23204616.

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. 2011;475(7354):1-8. doi: 10.1038/nature10236.

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 [internet]. Nature. 2011;475(7354):65-70. doi: 10.1038/nature10236, PMID 21697825.

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. Drugs/DB15220; 2018. Available from: https://go.drugbank.com. [Last accessed on 15 Aug 2019].

Stoddard BL, Fox KR. Editorial: Preprints, citations and nucleic acids research. Nucleic Acids Res. 2019;47(1):1-2. doi: 10.1093/nar/gky1229. PMID 30629263.

Nugraha G. GitHub [internet]. Github; 2021. Available from: https://github.com/nugrahagerry/hHRH4. [Last accessed on 23 Nov 2021]

Land H, Humble MS. YASARA: a tool to obtain structural guidance in biocatalytic investigations. Methods Mol Biol. 2018;1685:43-67. doi: 10.1007/978-1-4939-7366-8_4, PMID 29086303.

Cortes Benitez 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;210:105846. doi: 10.1016/j.jsbmb.2021.105846, PMID 33609690.

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):38-47. doi: 10.1124/mol.62.1.38, PMID 12065753.

Lengauer T, Rarey M. Computational methods for biomolecular docking. Curr Opin Struct Biol. 1996;6(3):402-6. doi: 10.1016/s0959-440x(96)80061-3, PMID 8804827.

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 a molecular docking prediction. Int J App Pharm. 2022;14(2):256-66. doi: 10.22159/ijap.2022v14i2.43784.

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

Zhang QY, Aires-de-Sousa J. Optimizing fragment and scaffold docking by use of molecular interaction fingerprints. Random forest prediction of mutagenicity from empirical physicochemical descriptors. J Chem Inf Model. 2007;47(1):1-8. doi: 10.1021/ci050520j, PMID 17238242.

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

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.