In silico ADME and molecular simulation studies of pharmacological activities of phytoconstituents of Annona muricata (L.) Fruit

Annona muricata Lin is known for its ethnomedicinal uses as food, decoctions, or infusions to address various conditions like skin infections, fever, diabetes, insomnia, malaria, hypertension, nervous disorders, diarrhea, and cancer. The study aimed to analyze the phytochemicals such as acetogenins, alkaloids, cyclopeptides, and flavonoids, present in A. muricata fruit, evaluate their pharmacokinetics, and understand binding dynamics with key molecular targets relevant to human well-being. Results indicated a mix of high and low gastrointestinal absorption (GIA) among A. muricata phytochemicals, with some demonstrating blood-brain barrier (BBB) permeability. Molecular target prediction highlighted frequent interactions with Programmed cell death protein 4 (PDCD4). Protein-protein interaction analysis revealed central connectivity of tyrosinase (TYR), Tyrosine 3-monooxygenase (TH), interleukin 2 (IL2), and others. Molecular docking results identified Luteolin 3,7-di-O-glucoside with the highest binding affinity for PDCD4 (−7.65 kcal.mol−1), followed by Annonaine (−7.294 kcal.mol−1); meanwhile, Dexamethasone (standard compound) exhibited a binding affinity of −6.682 kcal.mol−1. Molecular dynamic simulation indicated a stable binding energy ΔGbind (Total) for the Annonaine - PDCD4 complex (−35.851 kcal.mol−1) and Dexamethasone - PDCD4 complex (−28.489 kcal.mol−1). In conclusion, this study suggests potential anticancer properties of A. muricata based on modulation of PDCD4 protein, influencing the CDK/Akt/STAT3 pathway. Further in vivo investigations are necessary to validate these findings.