411 The Journal of Phytopharmacology 2023; 12(6):411-420 Online at: www.phytopharmajournal.com Research Article ISSN 2320-480X JPHYTO 2023; 12(6): 411-420 November- December Received: 02-10-2023 Accepted: 24-12-2023 ©2023, All rights reserved doi: 10.31254/phyto.2023.12607 Ololade Zacchaeus S Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria Lajide Labunmi Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria Onifade Olayinka F Department of Chemical Sciences, Biochemistry Unit, Bells University of Technology, Ota, Nigeria Eze John C Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria Tommy Bessie E Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria Orodepo Gabriel O Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria Idowu Olaniyi O Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria Oyebanji Olawumi T Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria Olaniran Anikeola C Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria Correspondence: Dr. Ololade Zacchaeus S Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria Email: sololade@unimed.edu.ng Exploration of Secondary Metabolites in Flower-Petal Annona muricata as Agonists for Peroxisome Proliferator- Activated Receptor-Alpha (PPARα) for Liver Function Ololade Zacchaeus S, Lajide Labunmi, Onifade Olayinka F, Eze John C, Tommy Bessie E, Orodepo Gabriel O, Idowu Olaniyi O, Oyebanji Olawumi T, Olaniran Anikeola C ABSTRACT The expression of PPARα in the liver is significantly increased in both non-alcoholic fatty liver disease (NAFLD) patients and experimental models. Animal studies have shown promising outcomes in improving histological conditions, such as fibrosis, through the use of PPARα agonists. This particular petal to act as agonists for PPARα. Molecular docking and Prime MM-GBSA (Molecular Mechanics- Generalized Born Surface Area) were employed to analyze the ligand binding affinity, atomistic interactions, and protein stability. Additionally, we conducted evaluations of the identified PPARα agonist candidates to assess their toxicity and pharmacological profiles were conducted. The hit compounds exhibit favourable binding affinity and thermodynamics stability, and interact effectively with key residues in the binding site. Furthermore, the safety assessment indicates minimal to non-acute toxicity and favourable drug-like properties for these compounds. Secondary metabolites in the extract are potential drug candidate. They demonstrate drug-like properties as they adhere to the Lipinski rule. Keywords: Annona muricata, Flower-petal, Phytochemicals, PPARα, ADMET, Liver function, Lipinski rule. INTRODUCTION Natural products from medicinal plants are good sources for deriving phytochemical for drug development [1-3] . Phytochemicals have been produced in the various environment, which represents an alternative resource for new drugs used to treat diseases [4-6] . Natural products remain as a leading source for the development of pharmaceuticals [6-8] . Annona muricata (sour sop) is a medicinal plant known as a natural multipurpose phytotherapy agent [9,10] . A. muricata is locally used to treat mesenteric lymphadentis, gastrointerstinal disorders, fever, rheumatoid, gouty, joints pain, skin ailments, tuberculosis, nausea, neurological disorders, bacterial and fungal infections, respiratory illnesses, diabetes, parasites and so on [10,11] . Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα Peroxisome proliferator-activated receptor-α (PPARα) is a nuclear hormone receptor which regulates the oxidation and transport of fatty acids. Upon activation it binds as a heterodimer with retinoid X receptor (RXR) to peroxisome response elements in genes involved in fatty acid oxidation. PPARα/γ activation might decrease the hepatic lipid accumulation, oxidative stress and inflammatory cytokine production [12-14] . Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. In liver, PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer [15-17] . To the best of our knowledge, there is paucity information on the use of phytochemicals as agonists for peroxisome proliferator-activated receptor-alpha (PPARα) so far. This study assessed their agonistic properties by comparing their binding affinity, binding interactions, and binding energy to a known agonist, fenofibrate and saroglitazar. Therefore, the research showcased the exploration of secondary metabolites in flower-petal extract of A. muricata as agonists for peroxisome proliferator-activated receptor-alpha (PPARα) for liver function. MATERIALS AND METHODS Protein retrieval and preparation The 3D crystal structure of Peroxisome proliferator-activated receptor alpha (PPARα) was obtained from the Protein Data Bank (PDB ID = 2ZNN) via their website (http://www.rcsb.org/pdb). The protein was prepared and visualized using the Protein Preparation Wizard panel in the Schrödinger Maestro suite 11.5 [18] . The preparation involved filling in missing loops and side chains using Prime, establishing