Sains Malaysiana 52(3)(2023): 899-939

http://doi.org/10.17576/jsm-2023-5203-17

Exploration of Annona muricata (Annonaceae) in the Treatment of Hyperlipidemia Through Network Pharmacology and Molecular Docking

(Penerokaan Annona muricata (Annonaceae) dalam Rawatan Hiperlipidemia Melalui Rangkaian Farmakologi dan Dok Molekul)

RENY SYAHRUNI¹, ABDUL HALIM UMAR^1,*, HINDRIYANI NURUL RAHMAN¹ & WISNU ANANTA KUSUMA²

¹Division of Pharmaceutical Biology, College of Pharmaceutical Sciences Makassar (Sekolah Tinggi Ilmu Farmasi Makassar), Jalan Perintis Kemerdekaan Km. 13.7 Daya, Makassar 90242, Indonesia

²Department of Computer Science, Faculty of Mathematics and Natural Sciences, Jalan Meranti-Dramaga Campus, IPB University, Bogor 16680, Indonesia

Received: 11 August 2022/Accepted: 5 January 2023

Abstract

Soursop (Annona muricata L.) is one of the plants that have antihyperlipidemic effects, but its underlying mechanism of action remains unknown. Previous investigations used TCMSP, KNApSAcK, ETCM, SwissTargetPrediction, SuperPred, CTD, and TTD to identify potential targets of soursop as antihyperlipidemic. Therefore, this study aims to explore soursop active compounds and demonstrate their mechanisms against hyperlipidemia through network pharmacology and molecular docking. OB and drug-likeness properties of the compounds from A. muricata were screened based on Lipinski’s Ro5 (Lipinski’s Rule of Five) parameters. Subsequently, the network of the compound–target–disease–pathways was constructed using Cytoscape. The target PPI (protein-protein interaction) network was built using STRING and the core targets were analyzed using GO with KEGG. The main active compounds against the targets were confirmed by molecular docking analysis. Based on the results, 158 compounds were identified in A. muricata, and the human body was found to absorb 56. It was discovered that 20 compounds were associated with cholesterol disease. The highest degree of the disease pathway of target compounds disease was annomuricin, XDH, myocardial ischemia, and metabolic pathways, respectively. The PPI showed GAPDH (glyceraldehyde-3-phosphate dehydrogenase) protein also has the highest degree. BP, CC, MF, and KEEG enrichments that play important roles are the response to drugs, plasma membranes, protein binding, and metabolic pathways. The molecular docking experiment confirmed the correlation between ligands and receptors (quercetin-XDH, coclaurine-ADRB3, fisetin, and robinetin-XDH) with binding energies of –9.3; –8.9; and –8.8 kcal   mol^–1, respectively. The interactions between ligands and receptors are hydrogen, alkyl, Pi-alkyl, Pi-sigma, and van der Waals bonds. It was discovered that A. muricata provided therapeutic effects, involving multi-compounds, multi-targets, multi-diseases, and multi-pathways as well as deep insight into the pathogenesis of hyperlipidemia. This can be used to design new drugs and develop novel therapies to treat hyperlipidemia.

Keywords: AMPK signaling; antihyperlipidemia; herbal medicine; phytochemicals; soursop

Abstrak

Durian belanda (Annona muricata L.) adalah salah satu tumbuhan yang mempunyai kesan antihiperlipidemik, tetapi mekanisme tindakan asasnya masih tidak diketahui. Penyelidikan sebelumnya menggunakan TCMSP, KNApSAcK, ETCM, SwissTargetPrediction, SuperPred, CTD dan TTD untuk mengenal pasti sasaran potensi durian belanda sebagai antihiperlipidemik. Oleh itu, kajian ini bertujuan untuk meneroka sebatian aktif durian belanda dan menunjukkan mekanismenya terhadap hiperlipidemia melalui rangkaian farmakologi dan dok molekul. OB dan sifat keserupaan dadah bagi sebatian daripada A. muricata telah disaring berdasarkan parameter Lipinski's Ro5 (Lipinski's Rule of Five). Selepas itu, rangkaian sebatian-sasaran-penyakit-laluan dibina menggunakan Cytoscape. Rangkaian sasaran PPI (interaksi protein-protein) dibina menggunakan STRING dan sasaran teras dianalisis menggunakan GO dengan KEGG. Sebatian aktif utama terhadap sasaran telah disahkan oleh analisis dok molekul. Berdasarkan keputusan, 158 sebatian dikenal pasti dalam A. muricata dan tubuh manusia didapati menyerap 56. Didapati bahawa 20 sebatian dikaitkan dengan penyakit kolesterol. Peratusan tertinggi laluan penyakit, penyakit sebatian sasaran masing-masing ialah annomuricin, XDH, iskemia miokardium dan laluan metabolik. PPI menunjukkan protein GAPDH (glyceraldehyde-3-phosphate dehydrogenase) juga mempunyai peratusan tertinggi. Pengayaan BP, CC, MF dan KEEG yang memainkan peranan penting ialah tindak balas terhadap ubat, membran plasma, pengikatan protein dan laluan metabolik. Uji kaji dok molekul mengesahkan korelasi antara ligan dan reseptor (quercetin-XDH, coclaurine-ADRB3, fisetin, dan robinetin-XDH) dengan tenaga mengikat masing-masing -9.3; –8.9; dan –8.8 kcal mol^–1. Interaksi antara ligan dan reseptor ialah ikatan hidrogen, alkil, Pi-alkil, Pi-sigma dan van der Waals. Didapati bahawa A. muricata memberikan kesan terapeutik, melibatkan pelbagai sebatian, pelbagai sasaran, pelbagai penyakit dan pelbagai laluan serta pandangan mendalam tentang patogenesis hiperlipidemia. Ini boleh digunakan untuk mereka bentuk ubat baharu dan membangunkan terapi baru untuk merawat hiperlipidemia.

Kata kunci: Antihiperlipidemia; durian belanda; fitokimia; pengisyaratan AMPK; ubat herba

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^*Corresponding author; email: ahuhalim76@yahoo.com