Studi In Silico dan Prediksi Farmakokinetik Senyawa Dibenzalaseton pada Reseptor ERK-1 sebagai Kandidat Antiinflamasi pada Aterosklerosis
Bilah Samping Artikel
Isi Artikel Utama
Abstrak
Aterosklerosis adalah masalah kesehatan global utama yang menjadi penyumbang penyebab terbesar dari penyakit kardiovaskular yang disebabkan oleh peradangan kronis pada dinding arteri. Dibenzalaseton (DBA) merupakan senyawa analog kurkumin yang mempunyai aktivitas potensial terhadap inflamasi kronis. Penelitian ini bertujuan untuk mengetahui potensi DBA sebagai penghambat inflamasi aterosklerosis pada reseptor ERK-1 dan mengetahui profil farmakokinetik dari senyawa DBA. Senyawa DBA didapatkan melalui PubChem dan dilakukan proses penambatan senyawa DBA pada struktur ERK-1 manusia (PDB ID: 4QTB) dengan menggunakan 3 tools docking yang berbeda yaitu Autodock, DockThor, dan Autodock Vina. Hasil studi secara in silico didapatkan energi ikatan masing-masing sebesar -7,97, -8,181, dan -9,6 kkal/mol dengan pengikatan hidrofobik ke ERK-1 melalui ARG84 di AutoDock , VAL 56, ARG84 di DockThor, dan VAL56, ALA69, LEU173 di AutoDock Vina. Prediksi sifat farmakokinetik dilakukan dengan web SWISS ADME yang menghasilkan bahwa senyawa DBA memiliki bioavailabilitas baik dengan penyerapan GI tinggi. Dengan demikian, hasil keseluruhan menunjukkan bahwa energi pengikatan dan interaksi residu tepat menggarisbawahi konformasi pengikatan DBA yang kuat dan menguntungkan, hal ini penting sebagai potensi terhadap kemanjuran terapeutik senyawa tersebut.
Unduhan
Rincian Artikel
Artikel ini berlisensi Creative Commons Attribution 4.0 International License.
Referensi
D. M. Tanase et al., “Portrayal of NLRP3 Inflammasome in Atherosclerosis: Current Knowledge and Therapeutic Targets,” Int. J. Mol. Sci., vol. 24, no. 9, p. 8162, May 2023, doi: 10.3390/ijms24098162.
P. Song et al., “Global and regional prevalence, burden, and risk factors for carotid atherosclerosis: a systematic review, meta-analysis, and modelling study,” Lancet Glob. Heal., vol. 8, no. 5, pp. e721–e729, 2020, doi: 10.1016/S2214-109X(20)30117-0.
P. Libby, “The changing landscape of oksi7855, pp. 524–533, 2021, doi: 10.1038/s41586-021-03392-8.
G. A. Mensah et al., “Global Burden of Cardiovascular Diseases and Risks, 1990-2022,” J. Am. Coll. Cardiol., vol. 82, no. 25, pp. 2350–2473, 2023, doi: 10.1016/j.jacc.2023.11.007.
A. Mehta et al., “Premature atherosclerotic peripheral artery disease: An underrecognized and undertreated disorder with a rising global prevalence,” Trends Cardiovasc. Med., vol. 31, no. 6, pp. 351–358, 2021, doi: 10.1016/j.tcm.2020.06.005.
P. Libby et al., “Atherosclerosis,” Nat. Rev. Dis. Prim., vol. 5, no. 1, pp. 1–18, 2019, doi: 10.1038/s41572-019-0106-z.
U. Moens, S. Kostenko, and B. Sveinbjørnsson, “The role of mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammation,” Genes (Basel)., vol. 4, no. 2, pp. 101–133, 2013, doi: 10.3390/genes4020101.
J. Sun and G. Nan, “The extracellular signal-regulated kinase 1/2 pathway in neurological diseases: A potential therapeutic target (Review),” Int. J. Mol. Med., vol. 39, no. 6, pp. 1338–1346, 2017, doi: 10.3892/ijmm.2017.2962.
Z. Wei and H. T. Liu, “MAPK signal pathways in the regulation of cell proliferation in mammalian cells,” Cell Res., vol. 12, no. 1, pp. 9–18, 2002, doi: 10.1038/sj.cr.7290105.
M. Cargnello and P. P. Roux, “Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases,” Microbiol. Mol. Biol. Rev., vol. 75, no. 1, pp. 50–83, 2011, doi: 10.1128/mmbr.00031-10.
T. Kong, M. Liu, B. Ji, B. Bai, B. Cheng, and C. Wang, “Role of the Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway in Ischemia-Reperfusion Injury,” Front. Physiol., vol. 10, no. August, 2019, doi: 10.3389/fphys.2019.01038.
R. Ghosh, A. Alajbegovic, and A. V. Gomes, “NSAIDs and cardiovascular diseases: Role of reactive oxygen species,” Oxid. Med. Cell. Longev., vol. 2015, no. Table 1, 2015, doi: 10.1155/2015/536962.
A. H. Chou, H. C. Lee, C. C. Liao, H. P. Yu, and F. C. Liu, “ERK/NF-kB/COX-2 Signaling Pathway Plays a Key Role in Curcumin Protection against Acetaminophen-Induced Liver Injury,” Life, vol. 13, no. 11, 2023, doi: 10.3390/life13112150.
K. R. Francisco et al., “Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei,” Bioorganic Med. Chem. Lett., vol. 81, no. January, pp. 32–33, 2023, doi: 10.1016/j.bmcl.2023.129123.
K. H. Lee et al., “Synthesis and biological evaluation of curcumin-like diarylpentanoid analogues for anti-inflammatory, antioxidant and anti-tyrosinase activities,” Eur. J. Med. Chem., vol. 44, no. 8, pp. 3195–3200, 2009, doi: 10.1016/j.ejmech.2009.03.020.
J. Park and Y. T. Kim, “Erythronium japonicum alleviates inflammatory pain by inhibiting mapk activation and by suppressing nf-kb activation via erk/nrf2/ho-1 signaling pathway,” Antioxidants, vol. 9, no. 7, pp. 1–17, 2020, doi: 10.3390/antiox9070626.
E. Chainoglou and D. Hadjipavlou-Litina, “Curcumin analogues and derivatives with anti-proliferative and anti-inflammatory activity: Structural characteristics and molecular targets,” Expert Opin. Drug Discov., vol. 14, no. 8, pp. 821–842, 2019, doi: 10.1080/17460441.2019.1614560.
N. M. P. Susanti, N. P. L. Laksmiani, N. K. M. Noviyanti, K. M. Arianti, and I. K. Duantara, “MOLECULAR DOCKING TERPINEN-4-OL SEBAGAI ANTIINFLAMASI PADA ATEROSKLEROSIS SECARA IN SILICO,” J. Kim., p. 221, Jul. 2019, doi: 10.24843/jchem.2019.v13.i02.p16.
M. R. R. Rahardhian, Y. Susilawati, I. Musfiroh, R. M. Febriyanti, Muchtaridi, and S. A. Sumiwi, “in Silico Study of Bioactive Compounds From Sungkai (Peronema Canescens) As Immunomodulator,” Int. J. Appl. Pharm., vol. 14, no. Special Issue 4, pp. 135–141, 2022, doi: 10.22159/ijap.2022.v14s4.PP33.
Indah Kurnia Klara, R. M. Purwono, and P. Achmadi, “Analisis In Silico Senyawa Flavonoid Kayu Secang (Caesalpinia sappan L.) pada Reseptor alpha Amilase Sebagai Antihiperglikemik,” Acta Vet. Indones., vol. 11, no. 3, pp. 210–219, 2023, doi: 10.29244/avi.11.3.210-219.
D. K. Dwi, R. Sasongkowati, and E. Haryanto, “Studi in Silico Sifat Farmakokinetik, Toksisitas, Dan Aktivitas Imunomodulator Brazilein Kayu Secang Terhadap Enzim 3-Chymotrypsin-Like Cysteine Protease Coronavirus,” J. Indones. Med. Lab. Sci., vol. 1, no. 1, pp. 76–85, 2020, doi: 10.53699/joimedlabs.v1i1.14.
J. Y. Kim, K. J. Jung, J. S. Choi, and H. Y. Chung, “Modulation of the age-related nuclear factor-kB (NF-kB) pathway by hesperetin,” Aging Cell, vol. 5, no. 5, pp. 401–411, 2006, doi: 10.1111/j.1474-9726.2006.00233.x.
Q. Guo et al., “NF-kB in biology and targeted therapy: new insights and translational implications,” Signal Transduct. Target. Ther., vol. 9, no. 1, 2024, doi: 10.1038/s41392-024-01757-9
Y. P. Hu et al., “Reactive Oxygen Species Mediated Prostaglandin E2 Contributes to Acute Response of Epithelial Injury,” Oxid. Med. Cell. Longev., vol. 2017, 2017, doi: 10.1155/2017/4123854.
S. Hall-Swan, D. Devaurs, M. M. Rigo, D. A. Antunes, L. E. Kavraki, and G. Zanatta, “DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins,” Comput. Biol. Med., vol. 139, no. September, p. 104943, 2021, doi: 10.1016/j.compbiomed.2021.104943.
E. H. B. Maia, L. R. Medaglia, A. M. Da Silva, and A. G. Taranto, “Molecular Architect: A User-Friendly Workflow for Virtual Screening,” ACS Omega, vol. 5, no. 12, pp. 6628–6640, 2020, doi: 10.1021/acsomega.9b04403.
Y. C. Martin, “A bioavailability score,” J. Med. Chem., vol. 48, no. 9, pp. 3164–3170, 2005, doi: 10.1021/jm0492002.
H. E. Hashem, S. Ahmad, A. Kumer, and Y. El Bakri, “In silico and in vitro prediction of new synthesized N-heterocyclic compounds as anti-SARS-CoV-2,” Sci. Rep., vol. 14, no. 1, pp. 1–18, 2024, doi: 10.1038/s41598-024-51443-7.
D. E. V. Pires, T. L. Blundell, and D. B. Ascher, “pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures,” J. Med. Chem., vol. 58, no. 9, pp. 4066–4072, 2015, doi: 10.1021/acs.jmedchem.5b00104.