Molecular Docking Study of Flavonoid Compounds in The Guava Leaves (Psidium Guajava L.) Which Has Potential as Anti-Inflammatory COX-2 Inhibitors
DOI:
https://doi.org/10.31764/lf.v2i2.5487Keywords:
Molecular Docking, Autodock4, Psidium guajava L, Inhibitor Anti-inflammatory, COX-2, Flavonoids.Abstract
ABSTRAK
Inflamasi yang bersifat progresif cenderung akan merusak dan menimbulkan beberapa permasalahan dalam tubuh. Enzim COX-2 merupakan salah satu mediator yang berkontribusi besar dalam terjadinya inflamasi progresif. Penelitian secara eksperimental daun jambu biji (Psidium guajava L.) terbukti memiliki aktivitas anti-inflamasi diduga karena banyak terkandung senyawa flavonoid, namun masih belum ada penelitian aktivitasnya terhadap penghambatan COX-2 selektif. Tujuan dari penelitian ini yaitu untuk mengetahui potensi senyawa flavonoid memiliki aktivitas anti-inflamasi penghambat COX-2 selektif menggunakan uji penambatan molekul. Metode: 31 senyawa flavonoid daun jambu biji didapat dari studi literatur beberapa penelitian in-vitro dan kode protein ID: 6COX yang digunakan pada penelitian penambatan molekular ini dilakukan energi minimisasi terlebih dahulu. Selanjutnya digunakan software docking Autodock4 dengan metode semi-flexible dan Lamarckian Genetic Algorithm (LGA). Semua senyawa flavonoid juga dilakukan prediksi Absorpsi, Distribusi, Metabolisme, Ekskresi, Toksisitas (ADMET). Hasil: secara keseluruhan diperoleh semua 31 senyawa uji flavonoid daun jambu biji berpotensi sebagai inhibitor COX-2 dan beberapa senyawa uji diantaranya memiliki nilai docking ∆G terbaik yang berasal dari Epicatechin-3-O-Gallate sebesar -9,31 kcal/mol, disusul oleh Gallocatechin sebesar -8,97 kcal/mol serta Tamarixetin -8,83 kcal/mol. Residu asam amino SER 353, TYR 385, SER 530, GLN 192 dan ARG 120 juga banyak berkontibusi dalam terbentuknya ikatan hidrogen. Kesimpulan: Epicatechin-3-O-Gallate merupakan senyawa uji yang memiliki potensi besar sebagai anti-inflamasi inhibitor COX-2 selektif karena memiliki kekuatan dan kestabilan ikatan yang tinggi dengan energi docking terendah saat ditambatkan pada protein target.
Kata kunci: Penambatan Molekuler; Autodock4; Psidium guajava L; Antiinflamasi Inhibitor ; COX-2; Flavonoid.
ABSTRACT
Progressive inflammation tends to damage and cause several problems in the body. The COX-2 enzyme is one of the mediators that have a significant contribution to progressive inflammation. Experimental study, guava leaves (Psidium guajava L.), have anti-inflammatory activity, presumably because they contain many flavonoid compounds. However, the lack of those research on their action against selective COX-2 inhibition. The purpose of this study is to determine the potential for flavonoid compounds to have anti-inflammatory activity of selective COX-2 inhibitors using molecular docking. Method: 31 flavonoids compound of guava leaves found on some literature studies of a systematic literature review and protein code ID: 6COX used on this molecular docking study by applying minimization energy at first. Next, using Autodock4 docking software with semi-flexible and Lamarckian Genetic Algorithm (LGA) methods. All flavonoid compounds also used screening Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET) prediction. Results: Overall results obtained that all 31 compounds of guava leaf flavonoids can potentially be COX-2 inhibitors. One of them has the best docking value with ∆G from Epicatechin-3-O-Gallate of -9.31 kcal/mol is high than the Gallocatechin of -8.97 kcal/mol and -8.83 kcal/mol Tamarixetin. The amino acid residues SER 353, TYR 385, SER 530, GLN 192, and ARG 120 contributed significantly to form hydrogen bonds. Conclusions: Epicatechin-3-O-Gallate has significant potential as an anti-inflammatory selective COX-2 inhibitor because it has high bond strength and stability with the lowest energy binding when attached to the target protein.
Keyword: Molecular Docking; Autodock4; Psidium guajava L; Inhibitor Anti-inflammatory; COX-2; Flavonoids.
References
Abdillah, Muhammad Nur, Nefi Rofani Ilmah, and Andhika Bintang Mahardhika. 2017. “Penambatan Molekuler Senyawa Polifenolat Terhadap Enzim Reverse Transcriptase Sebagai Senyawa Antiretroviral (HIV-1).†JSTFI Indonesian Journal of Pharmaceutical Science and Technology 6(1):36–44.
Adelina, Rosa. 2014. "Molecular Docking Studies of Annomuricin E and Muricapentocin on Antiproliferation Activity." Pp. 32–36 in Jurnal Ilmu Kefarmasian Indonesia. Vol. 12.
Al-Sayed, Eman, and Mohamed M. Abdel-Daim. 2018. "Analgesic and Anti-Inflammatory Activities of Epicatechin Gallate from Bauhinia Hookeri." Drug Development Research 79(4):157–64. doi: https://doi.org/10.1002/ddr.21430.
Alagumuthu, Manikandan, Kulathu Iyer Sathiyanarayanan, and Sivakumar Arumugam. 2015. "Molecular Docking, Design, Synthesis, in Vitro Antioxidant and Anti-Inflammatory Evaluations of New Isoquinoline Derivatives." International Journal of Pharmacy and Pharmaceutical Sciences 7(12):200–208.
Anand, Vijaya, Manikandan, Vijaya Kumar, Sampath Kumar, Pushpa, and Agaath Hedina. 2016. "Phytopharmacological Overview of Psidium Guajava Linn." Pharmacognosy Journal 8(4):314–20. doi: https://doi.org/10.5530/pj.2016.4.3.
Barbalho, Sandra M., Flávia M. V Farinazzi-machado, Ricardo De Alvares Goulart, Anna Cláudia, Saad Brunnati, and Alda Maria Machado. 2012. “Psidium Guajava (Guava): A Plant of Multipurpose Medicinal Applications.†Medicinal & Aromatic Plants 01(04):1–6. doi: https://doi.org/10.4172/2167-0412.1000104.
Basumatary, Panchamita, Manas Das, Pranjan Barman, and Manisha Choudhury. 2018. "Molecular Docking Study of 2, 3-Dimethylmaleic Anhydride (3, 4-Dimethyl-2, 5-Furandione) as Anti-Inflammatory Agent." Trends in Bioinformatics 11(2):56–63. doi: https://doi.org/10.3923/tb.2018.56.63.
Chen, Linlin, Huidan Deng, Hengmin Cui, Jing Fang, Zhicai Zuo, Junliang Deng, Yinglun Li, Xun Wang, and Ling Zhao. 2018. "Inflammatory Responses and Inflammation-Associated Diseases in Organs." Oncotarget 9(6):7204–18. doi: https://doi.org/10.18632/oncotarget.23208.
Choi, Soo-Youn, Joon-Ho Hwang, Soo-Young Park, Yeong-Jun Jin, Hee-Chul Ko, Sang-Wook Moon, and Se-Jae Kim. 2008. "Fermented Guava Leaf Extract Inhibits LPS- Induced COX-2 and INOS Expression in Mouse Macrophage Cells by Inhibition of Transcription Factor NF-ΚB." Phytotherapy Research 22(4):1030–1034. doi: https://doi.org/10.1002/ptr.2419.
Curtis, Elizabeth, Nicholas Fuggle, Sarah Shaw, Laura Spooner, Georgia Ntani, Camille Parsons, Nadia Corp, Germain Honvo, Janis Baird, Stefania Maggi, Elaine Dennison, Olivier Bruyère, Jean Yves Reginster, and Cyrus Cooper. 2019. "Safety of Cyclooxygenase-2 Inhibitors in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis." Drugs and Aging 36(1):25–44. doi: https://doi.org/10.1007/s40266-019-00664-x.
D'mello, Priscilla, Manoj Kumar Gadhwal, Urmila Joshi, and Preetam Shetgiri. 2011. "Modeling of COX-2 Inhibitory Activity of Flavonoids." International Journal of Pharmacy and Pharmaceutical Sciences 3(4):33–40.
Desai, Shreena J., Ben Prickril, and Avraham Rasooly. 2018. "Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer." Nutrition and Cancer 70(3):350–75. doi: https://doi.org/10.1080/01635581.2018.1446091.
El-Araby, Moustafa, Abdelsattar Omar, Hassanein H. Hassanein, Abdel Ghany H. El-Helby, and Asharf A. Abdel-Rahman. 2012. "Design, Synthesis and in Vivo Anti-Inflammatory Activities of 2,4-Diaryl-5-4H-Imidazolone Derivatives." Molecules 17(10):12262–75. doi: https://doi.org/10.3390/molecules171012262.
Fuhrmann, Jan, Alexander Rurainski, Hans-Peter Lenhof, and Dirk Neumann. 2010. "A New Lamarckian Genetic Algorithm for Flexible Ligand-Receptor Docking." Journal of Computational Chemistry 31(9):1911–1918. doi: https://doi.org/10.1002/jcc.21478.
Fujita, Hiroki, Masafumi Kakei, Hiromi Fujishima, Tsukasa Morii, Yuichiro Yamada, Zhonghua Qi, and Matthew D. Breyer. 2007. "Effect of Selective Cyclooxygenase-2 (COX-2) Inhibitor Treatment on Glucose-Stimulated Insulin Secretion in C57BL/6 Mice." Biochemical and Biophysical Research Communications 363(1):37–43. doi: 10.1016/j.bbrc.2007.08.090.
Guan, Pei Pei, and Pu Wang. 2019. "Integrated Communications between Cyclooxygenase-2 and Alzheimer's Disease." The FASEB Journal 33(1):1–21. doi: https://doi.org/10.1096/fj.201800355RRRR.
Gürbüz, Perihan, Şengül Dilem Doğan, Gizem Nur Çelik, Hatice Bekci, Ahmet Cumaoğlu, Miyase Gözde Gündüz, and Mehmet Yavuz Paksoy. 2019. “Bioactivity-Guided Isolation of Anti-Inflammatory Principles from Cistus Parviflorus Lam.†Records of Natural Products 13(3):226–35. doi: https://doi.org/10.25135/RNP.106.18.09.883.
Habtemariam, Solomon. 2019. The Chemical and Pharmacological Basis of Guava (Psidium Guajava L.) as Potential Therapy for Type 2 Diabetes and Associated Diseases. Elsevier Ltd.
Harisna, Azza Hanif, Rizky Nurdiansyah, Putri Hawa Syaifie, Dwi Wahyu Nugroho, Kurniawan Eko Saputro, Firdayani, Chandra Dwi Prakoso, Nurul Taufiqu Rochman, Nurwenda Novan Maulana, Alfian Noviyanto, and Etik Mardliyati. 2021. "In Silico Investigation of Potential Inhibitors to Main Protease and Spike Protein of SARS-CoV-2 in Propolis." Biochemistry and Biophysics Reports 26:1–13. doi: https://doi.org/10.1016/j.bbrep.2021.100969.
Hussein, R. K., and H. M. Elkhair. 2021. "Molecular Docking Identification for the Efficacy of Some Zinc Complexes with Chloroquine and Hydroxychloroquine against Main Protease of COVID-19." Journal of Molecular Structure 1231:1–9. doi: https://doi.org/10.1016/j.molstruc.2021.129979.
Iheagwam, Franklyn Nonso, Olubanke Olujoke Ogunlana, Oluseyi Ebenezer Ogunlana, Itunuoluwa Isewon, and Jelili Oyelade. 2019. "Potential Anti-Cancer Flavonoids Isolated from Caesalpinia Bonduc Young Twigs and Leaves: Molecular Docking and in Silico Studies." Bioinformatics and Biology Insights 13:1–16. doi: https://doi.org/10.1177/1177932218821371.
Jiang, Lirong, Junyu Lu, Yue Qin, Weirong Jiang, and Yanping Wang. 2020. "Antitumor Effect of Guava Leaves on Lung Cancer: A Network Pharmacology Study." Arabian Journal of Chemistry. doi: https://doi.org/10.1016/j.arabjc.2020.09.010.
Kartasasmita, Rahmana Emran, Rina Anugrah, and Daryono Hadi Tjahjono. 2015. “Kajian Docking Dan Prediksi Beberapa Aspek Farmakokinetika Desain Molekul Turunan Kuinin Sebagai Upaya Menemukan Kandidat Senyawa Antimalaria Yang Baru.†Kartika Jurnal Ilmiah Farmasi 3(1):6–13. doi: https://doi.org/10.26874/kjif.v3i1.13.
Kelutur, Faruk Jayanto, Resmi Mustarichie, and Abdul Kakhar Umar. 2020. “Virtual Screening Kandungan Senyawa Kipas Laut (Gorgonia Mariae) Sebagai Anti-Asma.†ALCHEMY Jurnal Penelitian Kimia 16(2):199–210. doi: https://doi.org/10.20961/alchemy.16.2.3996.199-210.
Meenambiga, Setti Sudharsan, Kalyanaraman Rajagopal, and R. Durga. 2015. "In Silico Docking Studies on the Components of Inonotus Sp., a Medicinal Mushroom against Cyclooxygenase-2 Enzyme." Asian Journal of Pharmaceutical and Clinical Research 8(3):142–45.
Nisha, Chaluveelaveedu Murleedharan, Ashwini Kumar, Prateek Nair, Nityasha Gupta, Chitrangda Silakari, Timir Tripathi, and Awanish Kumar. 2016. "Molecular Docking and In Silico ADMET Study Reveals Acylguanidine 7a as a Potential Inhibitor of B-Secretase." Advances in Bioinformatics 2016:1–6. doi: https://doi.org/10.1155/2016/9258578.
Nurtamin, Tomy, I. Putu Sudayasa, and Tien. 2018. "In Vitro Anti-Inflammatory Activities of Ethanolic Extract Elephantopus Scaber Leaves." Jurnal Kedokteran Dan Kesehatan Indonesia 9(1):46–52. doi: https://doi.org/10.20885/JKKI.Vol9.Iss1.art9.
Oo, Adrian, Pouya Hassandarvish, Sek Peng Chin, Vannajan Sanghiran Lee, Sazaly Abu Bakar, and Keivan Zandi. 2016. "In Silico Study on Anti-Chikungunya Virus Activity of Hesperetin." PeerJ (10):1–23. doi: https://doi.org/10.7717/peerj.2602.
Park, Hee Jo, Seung Jun Lee, Joon Cho, Amal Gharbi, Hee Dong Han, Tae Heung Kang, Yangmee Kim, Yeongjoon Lee, Won Sun Park, In Duk Jung, and Yeong Min Park. 2018. "Tamarixetin Exhibits Anti-Inflammatory Activity and Prevents Bacterial Sepsis by Increasing IL-10 Production." Journal of Natural Products 81(6):1435–43. doi: https://doi.org/10.1021/acs.jnatprod.8b00155.
Pires, Douglas E. V., Tom L. Blundell, and David B. Ascher. 2015. "PkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures." Journal of Medicinal Chemistry 58(9):4066–72. doi: https://doi.org/10.1021/acs.jmedchem.5b00104.
Pires, Douglas E. V, Tom L. Blundell, and David B. Ascher. 2015. "PkCSM : Predicting Small-Molecule Pharmacokinetic Properties Using Graph-Based Signatures (Theory- How to Enterpret PkCSM Result)." PKCSM 5.
Pranowo, Harno Dwi. 2009. “Peran Kimia Komputasi Dalam Desain Molekul Obat.†Pidato Pengukuhan JabatanGuru Besar Pada FakultasMatematika Dan Ilmu Pengetahuan Alam Universitas Gadjah Mada.
Ricciotti, Emanuela, and Garret A. Fitzgerald. 2011. “Prostaglandins and Inflammation.†Arteriosclerosis, Thrombosis, and Vascular Biology 31(5):986–1000. doi: https://doi.org/10.1161/ATVBAHA.110.207449.
Roy, Kunal, Supratik Kar, and Rudra Narayan Das. 2015. Understanding the Basics of QSAR for Applications in Pharmaceutical Sciences and Risk Assessment.
Satyanarayana, Sadam D. V., M. S. R. Krishna, Pindi Pavan Kumar, and Sirisha Jeereddy. 2018. "In Silico Structural Homology Modeling of Nif A Protein of Rhizobial Strains in Selective Legume Plants." Journal of Genetic Engineering and Biotechnology 16(2):731–37. doi: https://doi.org/10.1016/j.jgeb.2018.06.006.
Sen, Shib Sankar, V. Sukumaran, Sib Sankar Giri, and Se Chang Park. 2015. "Flavonoid Fraction of Guava Leaf Extract Attenuates Lipopolysaccharide-Induced Inflammatory Response via Blocking of NF-ΚB Signalling Pathway in Labeo Rohita Macrophages." Fish and Shellfish Immunology 47(1):85–92. doi: https://doi.org/10.1016/j.fsi.2015.08.031.
Sohilait, Mario Rowan, Harno Dwi Pranowo, and Winarto Haryadi. 2017. "Molecular Docking Analysis of Curcumin Analogues with COX-2." Bioinformation 13(11):356–59. doi: https://doi.org/10.6026/97320630013356
Suhadi, Andrio, Rizarullah Rizarullah, and Feriyani Feriyani. 2019. “Simulasi Docking Senyawa Aktif Daun Binahong Sebagai Inhibitor Enzyme Aldose Reductase.†Sel Jurnal Penelitian Kesehatan 6(2):55–65. doi: https://doi.org/10.22435/sel.v6i2.1651.
Thome, Angela Librianty, I. Ketut Sudiana, and Abu Bakar. 2019. "Psidium Guajava Leaves Compound As Anti-Inflammation: Systematic Review." Jurnal Natural 19(3):69–71. doi: https://doi.org/10.24815/jn.v19i3.13829.
Wati, Widia, Gunawan Pamudji Widodo, and Rina Herowati. 2020. "Prediction of Pharmacokinetics Parameter and Molecular Docking Study of Antidiabetic Compounds from Syzygium Polyanthum and Syzygium Cumini." Jurnal Kimia Sains Dan Aplikasi 23(6):189–95. doi: https://doi.org/10.14710/jksa.23.6.189-195.
Ya’u Ibrahim, Zakari, Adamu Uzairu, Gideon Shallangwa, and Stephen Abechi. 2020. "Molecular Docking Studies, Drug-Likeness and in-Silico ADMET Prediction of Some Novel β-Amino Alcohol Grafted 1,4,5-Trisubstituted 1,2,3-Triazoles Derivatives as Elevators of P53 Protein Levels." Scientific African 10:1–8. doi: https://doi.org/10.1016/j.sciaf.2020.e00570.
Yanuar, Arry, Muhammad Aditya Setiajid, and Hayun. 2014. “Analisis Penambatan Dan Simulasi Dinamika Molekular Komplex Siklooksigesinenase-2 Dengan Beberapa Senyawa Turunan Kuinazolinon.†Jurnal Farmasi Indonesia 7(1):50–59.
Yusuf, Muhammad, Ari Hardianto, Muchtaridi Muchtaridi, Rina F. Nuwarda, and Toto Subroto. 2018. Introduction of Docking-Based Virtual Screening Workflow Using Desktop Personal Computer. Vols. 1–3. Elsevier Ltd.
