PERTANIKA JOURNAL OF TROPICAL AGRICULTURAL SCIENCE

Current breakthroughs in molecular docking approaches have significantly contributed to discovering novel antagonists that competitively bind to histamine H1 receptor (H1R), thereby inhibiting histamine-mediated reactions. A reliable antagonist must possess a superior binding affinity with H1R compared to histamine while having the ability to be efficiently absorbed and traverse the intestinal barrier for systemic circulation. The consideration of human intestinal absorption (HIA) provides an extension for comprehending ligands' bioavailability before engaging in docking studies. In this study, the Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) model was utilized to predict the HIA of the ligands, followed by molecular docking to target the H1R with compounds presented in Malaysian Kelulut honey that are impenetrable to the blood-brain barrier (BBB-) by using a virtual screening tool, Pyrx. The findings highlighted the importance of specific residues, including ASP 107, TYR 108, SER 111, and TYR 431, in H1R, as they interact with histamine within the binding spaces, demonstrating strong intermolecular forces. Among 69 BBB- compounds, Polydatin (PD), Sophoflavescenol, and Dendrocandin B exhibited favorable results in docking studies with H1R, indicating their potential to be used as competitive antagonists in treating allergic symptoms. A more promising candidate can be nominated to develop optimal antagonists by addressing absorption properties and binding affinity perspectives.

• Adhav, V. A., & Saikrishnan, K. (2023). The realm of unconventional noncovalent interactions in proteins: Their significance in structure and function. ACS Omega, 8(25), 22268–22284. https://doi.org/10.1021/acsomega.3c00205
  
  Ahmed, S., Mahtarin, R., Ahmed, S. S., Akter, S., Islam, M. S., Mamun, A. Al, Islam, R., Hossain, M. N., Ali, M. A., Sultana, M. U. C., Parves, M. R., Ullah, M. O., & Halim, M. A. (2021). Investigating the binding affinity, interaction, and structure-activity-relationship of 76 prescription antiviral drugs targeting RdRp and Mpro of SARS-CoV-2. Journal of Biomolecular Structure and Dynamics, 39(16), 6290–6305. https://doi.org/10.1080/07391102.2020.1796804
  
  Akram, A., Su, C.-H., & Fu, C.-C. (2024). Targeting small druggable compounds against 3RZE histamine H1 receptor as potential of anti-allergic drug applying molecular modeling approach. Future Journal of Pharmaceutical Sciences, 10, 76. https://doi.org/10.1186/s43094-024-00646-w
  
  Aspar, M. M., Edros, R., & Hamzah, N. A. (2020). Antibacterial evaluation of malaysian kelulut, tualang and acacia honey against wound infecting bacteria. IOP Conference Series: Materials Science and Engineering, 991(1), 012065. https://doi.org/10.1088/1757-899X/991/1/012065
  
  Cevikbas, F., & Lerner, E. A. (2020). Physiology and pathophysiology of itch. Physiological Reviews, 100(3), 945–982. https://doi.org/10.1152/physrev.00017.2019
  
  Chaubah, M. A. L., Bontes, B. W., & Mulachelah, N. A. (2019). Molecular docking of polycyclic aromatic hydrocarbons as potentially carcinogenic molecules through binding with aryl hydrocarbon receptor. Journal of Smart Bioprospecting and Technology, 1(1), 12–15. https://doi.org/10.21776/ub.jsmartech.2019.001.01.3
  
  Chmiel, T., Mieszkowska, A., Kempińska-Kupczyk, D., Kot-Wasik, A., Namieśnik, J., & Mazerska, Z. (2019). The impact of lipophilicity on environmental processes, drug delivery and bioavailability of food components. Microchemical Journal, 146, 393–406. https://doi.org/10.1016/j.microc.2019.01.030
  
  Conrad, M., Horn, A. H. C., & Sticht, H. (2023). Computational analysis of histamine protonation effects on H1R binding. Molecules, 28(9), 3774. https://doi.org/10.3390/molecules28093774
  
  Daina, A., & Zoete, V. (2016). A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem, 11(11), 1117–1121. https://doi.org/10.1002/cmdc.201600182
  
  Dallakyan, S., & Olson, A. (2015). Small-molecule library screening by docking with PyRx. In J. Hempel, C. Williams & C. Hong (Eds.), Chemical biology: Methods in molecular biology (Vol. 1263, pp. 243–250). Humana Press. https://doi.org/10.1007/978-1-4939-2269-7_19
  
  Dereka, B., Yu, Q., Lewis, N. H. C., Carpenter, W. B., Bowman, J. M., & Tokmakoff, A. (2021). Crossover from hydrogen to chemical bonding. Science, 371(6525), 160–164. https://doi.org/10.1126/science.abe1951
  
  Edros, R., Feng, T. W., & Dong, R. H. (2023a). Utilizing machine learning techniques to predict the blood-brain barrier permeability of compounds detected using LCQTOF-MS in Malaysian Kelulut honey. SAR and QSAR in Environmental Research, 34(6), 475–500. https://doi.org/10.1080/1062936X.2023.2230868
  
  Edros, R., Feng, T. W., & Dong, R. H. (2023b). Utilizing machine learning techniques to predict the blood-brain barrier permeability of compounds detected using LCQTOF-MS in Malaysian Kelulut honey. SAR and QSAR in Environmental Research, 34(6), 475–500. https://doi.org/10.1080/1062936X.2023.2230868
  
  Feng, T. W., Edros, R., Ghani, N. A., Mokhtar, S. U., & Dong, R. (2024). Prediction of blood-brain barrier permeability of compounds by machine learning algorithms. Journal of Advanced Research in Applied Sciences and Engineering Technology, 33(2), 269–276. https://doi.org/10.37934/araset.33.2.269276
  
  Feng, Z., Hou, T., & Li, Y. (2013). Docking and MD study of histamine H4R based on the crystal structure of H1R. Journal of Molecular Graphics and Modelling, 39, 1–12. https://doi.org/10.1016/j.jmgm.2012.10.003
  
  Hamad, R. S. (2023). Rutin, a flavonoid compound derived from garlic, as a potential immunomodulatory and anti-inflammatory agent against murine Schistosomiasis mansoni. Nutrients, 15(5), 1206. https://doi.org/10.3390/nu15051206
  
  Ince, M., & Ruether, P. (2021). Histamine and antihistamines. Anaesthesia & Intensive Care Medicine, 22(11), 749–755. https://doi.org/https://doi.org/10.1016/j.mpaic.2021.07.025
  
  Kaliner, M. A., Oppenheimer, J., & Farrar, J. R. (2010). Comprehensive review of olopatadine: The molecule and its clinical entities. Allergy and Asthma Proceedings: The Official Journal of Regional and State Allergy Societies, 31(2), 112–119. https://doi.org/10.2500/aap.2010.31.3317
  
  Karami, A., Fakhri, S., Kooshki, L., & Khan, H. (2022). Polydatin: Pharmacological mechanisms, therapeutic targets, biological activities, and health benefits. Molecules, 27(19), 6474. https://doi.org/10.3390/molecules27196474
  
  Kikiowo, B., Ahmad, I., Alade, A. A., Ijatuyi, T. T., Iwaloye, O., & Patel, H. M. (2023). Molecular dynamics simulation and pharmacokinetics studies of ombuin and quercetin against human pancreatic α-amylase. Journal of Biomolecular Structure and Dynamics, 41(20), 10388–10395. https://doi.org/10.1080/07391102.2022.2155699
  
  Kok, Z. Y., Stoddart, L. A., Mistry, S. J., Mocking, T. A. M., Vischer, H. F., Leurs, R., Hill, S. J., Mistry, S. N., & Kellam, B. (2022). Optimization of peptide linker-based fluorescent ligands for the histamine H1 receptor. Journal of Medicinal Chemistry, 65(12), 8258–8288. https://doi.org/10.1021/acs.jmedchem.2c00125
  
  Laskar, Y. B., Mazumder, P. B., & Talukdar, A. D. (2023). Hibiscus sabdariffa anthocyanins are potential modulators of estrogen receptor alpha activity with favourable toxicology: A computational analysis using molecular docking, ADME/Tox prediction, 2D/3D QSAR and molecular dynamics simulation. Journal of Biomolecular Structure and Dynamics, 41(2), 611–633. https://doi.org/10.1080/07391102.2021.2009914
  
  Mehta, P., Miszta, P., & Filipek, S. (2021). Molecular modeling of histamine receptors—recent advances in drug discovery. Molecules, 26(6), 1778. https://doi.org/10.3390/molecules26061778
  
  Mohd, M. A., Edros, R., & Hamzah, N. A. (2020). Antibacterial properties of Kelulut, Tualang and Acacia honey against fourteen clinically-isolated strains of bacteria-infecting wound. AIP Conference Proceedings, 2252, 020001. https://doi.org/10.1063/5.0020300
  
  Rakha, A., Umar, N., Rabail, R., Butt, M. S., Kieliszek, M., Hassoun, A., & Aadil, R. M. (2022). Anti-inflammatory and anti-allergic potential of dietary flavonoids: A review. Biomedicine & Pharmacotherapy, 156, 113945. https://doi.org/10.1016/j.biopha.2022.113945
  
  Ramirez, D. A., Federici, M. F., Altamirano, J. C., Camargo, A. B., & Luco, J. M. (2021). Permeability data of organosulfur garlic compounds estimated by immobilized artificial membrane chromatography: Correlation across several biological barriers. Frontiers in Chemistry, 9, 690707. https://doi.org/10.3389/fchem.2021.690707
  
  Renz, H., & Skevaki, C. (2021). Early life microbial exposures and allergy risks: Opportunities for prevention. Nature Reviews Immunology, 21(3), 177–191. https://doi.org/10.1038/s41577-020-00420-y
  
  Riza, Y. M., Parves, M. R., Tithi, F. A., & Alam, S. (2019). Quantum chemical calculation and binding modes of H1R ; a combined study of molecular docking and DFT for suggesting therapeutically potent H1R antagonist. In Silico Pharmacology, 7(1), 1–9. https://doi.org/10.1007/s40203-019-0050-3
  
  Shukla, R., & Tripathi, T. (2020). Molecular dynamics simulation of protein and protein–ligand complexes. In D. B. Singh (Ed.), Computer-aided drug design (pp. 133–161). Springer Singapore. https://doi.org/10.1007/978-981-15-6815-2_7
  
  Tamura, T., Matsubara, M., Takada, C., Hasegawa, K., Suzuki, K., Ohmori, K., & Karasawa, A. (2004). Effects of olopatadine hydrochloride, an antihistamine drug, on skin inflammation induced by repeated topical application of oxazolone in mice. British Journal of Dermatology, 151(6), 1133–1142. https://doi.org/10.1111/j.1365-2133.2004.06172.x
  
  Tuksitha, L., Chen, Y.-L., Chen, Y.-L., Wong, K.-Y., & Peng, C.-C. (2018). Antioxidant and antibacterial capacity of stingless bee honey from Borneo (Sarawak). Journal of Asia-Pacific Entomology, 21(2), 563–570. https://doi.org/10.1016/j.aspen.2018.03.007
  
  Wang, Z., Bosma, R., Kuhne, S., van den Bor, J., Garabitian, W., Vischer, H. F., Wijtmans, M., Leurs, R., & de Esch, I. J. P. (2021). Exploring the effect of cyclization of histamine H1 receptor antagonists on ligand binding kinetics. ACS Omega, 6(19), 12755–12768. https://doi.org/10.1021/acsomega.0c06358
  
  Wu, C.-T., Huang, K.-S., Yang, C.-H., Chen, Y.-C., Liao, J.-W., Kuo, C.-L., Chen, C.-L., Lo, S.-F., Hsieh, C.-C., & Tsay, H.-S. (2014). Inhibitory effects of cultured Dendrobium tosaense on atopic dermatitis murine model. International Journal of Pharmaceutics, 463(2), 193–200. https://doi.org/10.1016/j.ijpharm.2013.08.015
  
  Xia, R., Wang, N., Xu, Z., Lu, Y., Song, J., Zhang, A., Guo, C., & He, Y. (2021). Cryo-EM structure of the human histamine H1 receptor/Gq complex. Nature Communications, 12, 2086. https://doi.org/10.1038/s41467-021-22427-2
  
  Xiao, Y., & Woods, R. J. (2023). Protein–Ligand CH−π Interactions: Structural Informatics, Energy Function Development, and Docking Implementation. Journal of Chemical Theory and Computation, 19(16), 5503–5515. https://doi.org/10.1021/acs.jctc.3c00300
  
  Ye, J., Piao, H., Jiang, J., Jin, G., Zheng, M., Yang, J., Jin, X., Sun, T., Choi, Y. H., Li, L., & Yan, G. (2017). Polydatin inhibits mast cell-mediated allergic inflammation by targeting PI3K/Akt, MAPK, NF-κB and Nrf2/HO-1 pathways. Scientific Reports, 7, 11895. https://doi.org/10.1038/s41598-017-12252-3
  
  Zekri, A., Harkati, D., Kenouche, S., Saleh, B. A., & Alnajjar, R. (2023). A computational study of potent series of selective estrogen receptor degraders for breast cancer therapy. Journal of Biomolecular Structure and Dynamics, 41(20), 11078–11100. https://doi.org/10.1080/07391102.2022.2159877
  
  Zhang, A., Meng, K., Liu, Y., Pan, Y., Qu, W., Chen, D., & Xie, S. (2020). Absorption, distribution, metabolism, and excretion of nanocarriers in vivo and their influences. Advances in Colloid and Interface Science, 284, 102261. https://doi.org/10.1016/j.cis.2020.102261
  
  Zhou, Z., An, Q., Zhang, W., Li, Y., Zhang, Q., & Yan, H. (2024). Histamine and receptors in neuroinflammation: Their roles on neurodegenerative diseases. Behavioural Brain Research, 465, 114964. https://doi.org/https://doi.org/10.1016/j.bbr.2024.114964