Identification of Manilkara zapota Phytochemicals as Novel RANKL Inhibitors for Osteoporosis Therapy: An Integrated Computational Study Iffat Syafiqoh Afif- Rahadian Zainul- Intan Elwis Khairina Muzia
(a) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Padang State University, Padang, Indonesia
Orcid: 0009-0000-7800-0260
(b) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Negeri Padang, Air Tawar Barat 25132, Padang, Indonesia.
Center for Advanced Material Processing, Artificial Intelligence, and Biophysics Informatics (CAMPBIOTICS), Universitas Negeri Padang, Air Tawar Barat 25132, Padang, Indonesia.
INTI International University, Negeri Sembilan, 71800, Malaysia.
Orcid: 0000-0002-3740-3597
(c) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Padang State University, Padang, Indonesia
Abstract
Osteoporosis remains a significant global health challenge characterized by systemic bone density depletion and heightened fracture risks. This condition necessitates the discovery of potent inhibitors for the RANKL (Receptor Activator of Nuclear Factor-kappa B Ligand) signaling pathway. Due to the adverse effects of synthetic therapeutics, this study investigated the anti-osteoporotic potential of ten bioactive compounds derived from Manilkara zapota. These compounds include betulinic acid, caffeic acid, chlorogenic acid, gallic acid, germanicol, L-arabinose, myricetin, beta-amyrin, myricetin-3-O-glucoside, and oleanolic acid. A systematic in silico approach was employed to evaluate these phytochemicals. Molecular docking simulations were performed against the RANKL protein (PDB ID: 3URF) using AutoDock Vina, with the monoclonal antibody Denosumab serving as the reference ligand. Quantitative results revealed that chlorogenic acid exhibited the most formidable binding affinity among the phytochemicals with a docking score of -5.4216 kcal/mol (RMSD 1.1338 A), followed by germanicol (-4.8063 kcal/mol- RMSD 1.6254 A) and myricetin (-4.3947 kcal/mol- RMSD 1.3269 A). Comparatively, Denosumab yielded a binding energy of -6.1829 kcal/mol. All tested compounds demonstrated high conformational stability with RMSD values consistently below the 2.0 A threshold. Furthermore, ADMET profiling and drug-likeness evaluations confirmed that the lead phenolic constituents strictly adhered to Lipinski^s Rule of Five, exhibiting favorable pharmacokinetic parameters and minimal predicted toxicity. These findings suggest that M. zapota phytochemicals, particularly chlorogenic acid, possess significant potential as natural RANKL inhibitors. This research provides a theoretical foundation for further in vitro and in vivo validations in developing plant-based alternatives for metabolic bone disease management.
