Pembuatan Protokol Penapisan Virtual Berbasis Stuktur (pvbs) untuk Identifikasi Ligan Inhibitor Reseptor Platelet-Activating Factor (PAF-r) sebagai Target Terapeutik Asma menggunakan YASARA

Gerry Nugraha, Enade Perdana Istyastono


Platelet-activating factor receptors (PAF-r) is known as one of the receptors that affect asthma, while the Y-21480 ligand is reported as an effective, specific, and active PAF-r antagonist for asthma patients. Research in building structure-based virtual screening protocol (SBVS) for identification of PAF-r ligand inhibitors has been performed, the receptor crystal structure was obtained from the Protein Data Bank (PDB ID: 5zkp), while the ligand used as a leading compound is Y-24180, obtained from U.S. National Library of Medicine. Interactions between ligands and receptors are observed through molecular dynamics simulations using the YASARA program at intervals up to 20 nanoseconds, ligand-receptor binding stability occurs after a time interval of 2 nanoseconds, the lowest ligand-receptor binding energy occurs at a time interval of 1,401 picoseconds. Internal validation by re-docking 1,000 times the ligand to receptor resulted in a value of Root Mean Square Deviation (RMSD) of 0.6037 Å,  confirmed that SBVS protocol was accurately able to reproduce the Y-24180 ligand pose on the 5zkp crystal structure,  the protocol can be used as a new approach for investigation or design of compounds that have therapeutic potential as anti-asthma.


Asthma; PAF-r, SBVS; in silico; molecular dynamics

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Network, G. A., The global asthma report 2018. Auckland, New Zealand, (2018).

Fergeson, J. E., Patel, S. S. & Lockey, R. F., Acute asthma, prognosis, and treatment. J. Allergy Clin. Immunol., 139(2): 438–447 (2017).

Kemenkes, R. I., Penderita Asma Indonesia. Pus. data dan Inf. kemenkes RI, 1–16 (2019).

Kasperska-Zajac, A., Brzoza, Z. & Rogala, B., Platelet-activating factor (PAF): A review of its role in asthma and clinical efficacy of PAF antagonists in the disease therapy. Recent Pat. Inflamm. Allergy Drug Discov., 2(1): 72–76 (2008).

Cuss, F., Dixon, C. . & Barnes, P., Effects of inhaled platelet activating factor on pulmonary function and bronchial responsiveness in man. Lancet, 328(8500): 189–192 (1986).

Kuitert, L. & Barnes, N. C., PAF and asthma—time for an appraisal? Clin. Exp. Allergy, 25(12): 1159–1162 (1995).

Pałgan, K. & Bartuzi, Z., Platelet activating factor in allergies. Int. J. Immunopathol. Pharmacol., 28(4): 584–589 (2015).

Chan-Yeung, M., Lam, S., Chan, H., Tse, K. S. & Salari, H., The release of platelet-activating factor into plasma during allergen-induced bronchoconstriction. J. Allergy Clin. Immunol., 87(3): 667–673 (1991).

Hozawa, S., Haruta, Y., Ishioka, S. & Yamakido, M., Effects of a PAF antagonist, Y-24180, on bronchial hyperresponsiveness in patients with asthma. Am. J. Respir. Crit. Care Med., 152(4): 1198–1202 (1995).

Demopoulos, C. A., Pinckard, R. N. & Hanahan, D. J., Platelet-activating factor. Evidence for 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine as the active component (a new class of lipid chemical mediators). J. Biol. Chem., 254(19): 9355–9358 (1979).

Demopoulos, C. A., Karantonis, H. C. & Antonopoulou, S., Platelet activating factor—a molecular link between atherosclerosis theories. Eur. J. Lipid Sci. Technol., 105(11): 705–716 (2003).

Tsoupras, A., Lordan, R. & Zabetakis, I., Inflammation, not cholesterol, is a cause of chronic disease. Nutrients, 10(5): 604 (2018).

da Silva-Jr, I. A., Chammas, R., Lepique, A. P. & Jancar, S., Platelet-activating factor (PAF) receptor as a promising target for cancer cell repopulation after radiotherapy. Oncogenesis, 6(1): e296–e296 (2017).

Lordan, R., Tsoupras, A. & Zabetakis, I., The potential role of dietary platelet-activating factor inhibitors in cancer prevention and treatment. Adv. Nutr., 10(1): 148–164 (2019).

Palur Ramakrishnan, A. V. K., Varghese, T. P., Vanapalli, S., Nair, N. K. & Mingate, M. D., Platelet activating factor: A potential biomarker in acute coronary syndrome? Cardiovasc. Ther., 35(1): 64–70 (2017).

Tsoupras, A. B., Chini, M., Tsogas, N., Fragopoulou, E., Nomikos, T., Lioni, A., Mangafas, N., et al., Anti-platelet-activating factor effects of highly active antiretroviral therapy (HAART): A new insight in the drug therapy of HIV infection? AIDS Res. Hum. Retroviruses, 24(8): 1079–1086 (2008).

Yost, C. C., Weyrich, A. S. & Zimmerman, G. A., The platelet activating factor (PAF) signaling cascade in systemic inflammatory responses. Biochimie, 92(6): 692–697 (2010).

Birkl, D., Quiros, M., García-Hernández, V., Zhou, D. W., Brazil, J. C., Hilgarth, R., Keeney, J., et al., TNFα promotes mucosal wound repair through enhanced platelet activating factor receptor signaling in the epithelium. Mucosal Immunol., 12(4): 909–918 (2019).

Suvarna, Y., Maity, N. & Shivamurthy, M. C., Emerging trends in retrograde signaling. Mol. Neurobiol., 53(4): 2572–2578 (2016).

Lordan, R., Tsoupras, A., Zabetakis, I. & Demopoulos, A. C., Forty years since the structural elucidation of platelet-activating factor (PAF): Historical, current, and future research perspectives. Molecules, 24(23): (2019).

Cao, C., Tan, Q., Xu, C., He, L., Yang, L., Zhou, Y., Zhou, Y., et al., Structural basis for signal recognition and transduction by platelet-activating-factor receptor. Nat. Struct. Mol. Biol., 25(6): 488–495 (2018).

Audet, M. & Stevens, R. C., Emerging structural biology of lipid G protein-coupled receptors. Protein Sci., 28(2): 292–304 (2019).

DiMasi, J. A., Hansen, R. W. & Grabowski, H. G., The price of innovation: New estimates of drug development costs. J. Health Econ., 22(2): 151–185 (2003).

Hinchliffe, A., Molecular modelling for beginners. John Wiley & Sons, Ltd, (2005).

Ekins, S., Mestres, J. & Testa, B., In silico pharmacology for drug discovery: Applications to targets and beyond. Br. J. Pharmacol., 152(1): 21–37 (2007).

Kagoshima, M., Tomomatsu, N., Iwahisa, Y., Yamaguchi, S., Kawakami, Y. & Terasawa, M., Effects of Y-24180, a long-acting and potent antagonist to platelet-activating factor, on immediate asthmatic response in guinea pigs. Pharmacology, 54(1): 1–7 (1997).

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

Schneider, G., De novo molecular design. John Wiley & Sons, Ltd, (2013).

Istyastono, E. P., Construction and optimization of structure-based virtual screening protocols to identify cyclooxygenase-1 inhibitors using open babel, spores and plants. Indones. J. Chem. Vol 12, No 2, (2012). doi:10.22146/ijc.21354

Marcou, G. & Rognan, D., Optimizing fragment and Scaffold docking by use of molecular interaction fingerprints. J. Chem. Inf. Model., 47(1): 195–207 (2007).

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