Stephenie Alaribe

Nigeria

In-silico and ADMET Analysis of Pseudocarpaine from Carica papaya as a Potential Multi-Target Anticancer Agent

Jolayemi Olaoluwa¹., Sarah Kutu 1., Andrew Okocha1., Owolabi, Rhoda Owolabi 1., Titilayo Blessing 1., Florence Nkemehule 2,4., Foluke Ayeni 3,4., Damilare Babatunde5,6, Nomampondo Magwa5, Sofidiya Margaret2,4., Gloria Ayoola and Stephenie Chinwe Alaribe¹,4*
¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Lagos, Idi-Araba, Lagos, Nigeria.
2 Department of Pharmacognosy, Faculty of Pharmacy, University of Lagos, Idi-Araba, Lagos, Nigeria.
3 Department of Clinical and Bio-Pharmacy, Faculty of Pharmacy, University of Lagos, Idi-Araba, Lagos, Nigeria.
4 Faculty of Pharmacy, Computational-Informatics Research Unit (FAPCRU), University of Lagos.
5 Department of Chemistry, University of South Africa, Florida Science Campus, Johannesburg, 1709, South Africa.
6 Centre for Materials Science, University of South Africa, Florida, 1710, Johannesburg, South Africa

Abstract

Background

Cancer is a complex and multifactorial disease, involving dysregulated cell signaling pathways that drive proliferation, survival, angiogenesis, and metastasis (Mir et al., 2024; Chen et al., 2025). Targeting multiple oncogenic pathways simultaneously is increasingly recognized as a strategic approach to enhance therapeutic efficacy and overcome drug resistance. Plant-derived natural products have long been a rich source of bioactive compounds with anticancer properties, offering chemical diversity and structural complexity that synthetic libraries may lack (BultumTolossa and Lee, 2022; Chen et al., 2025). Examples useful in cancer therapy include vincristine, paclitaxel, and camptothecin derivatives. Carica papaya has drawn increasing attention for its diverse pharmacological effects. Its alkaloid constituents, pseudocarpaine, structurally related to carpaine, exhibit potential cytotoxicity and structural features compatible with protein–ligand interactions crucial for cancer inhibition. It possesses a distinct macrocyclic dilactone framework that could enable selective binding across multiple cancer-related proteins whose binding characteristics and ADMET properties remain limited. This study investigates pseudocarpaine’s potential as a multi-target anticancer compound by assessing its molecular interactions with key oncogenic proteins alongside ADMET profiling to predict its pharmacokinetic and toxicity behavior.

Methods

The 3D structure of pseudocarpaine and standards(erlotinib, TTI-101, idelalisib, vorinostat, bortezomib, and venetoclax)were retrieved from PubChem. Protein structures for EGFR, STAT3, PI3K, NF-κB, HDAC2, and BCL-2 were downloaded from the Protein Data Bank (PDB).
Molecular docking was performed using Schrödinger Maestro(Release 2023-3)under the Glide XP precision mode. Proteins were prepared using the Protein Preparation Wizard, with missing side chains reconstructed. Docking results were analyzed based on GlideScores and hydrogen bond interactions.
ADMET properties were predicted using SwissADME and ProTox-III. Parameters evaluated included molecular weight, lipophilicity(LogP),hydrogen bond donors/acceptors, topological polar surface area (TPSA),gastrointestinal absorption, blood–brain barrier permeability, CYP450 enzyme inhibition, and synthetic accessibility. Toxicological endpoints and LD50 values were obtained from ProTox-III.

Results

Pseudocarpaine demonstrated notable binding affinity, particularly toward BCL-2 (docking score;4.55 kcal/mol;ΔG −44.47 kcal/mol), comparable to reference inhibitors. Its physicochemical and ADMET profile satisfied Lipinski’s Rule of Five, with high gastrointestinal absorption and no major CYP450 inhibition or predicted toxicity.

Conclusions

These findings highlight pseudocarpaine as a viable lead for further in vitro and in vivo evaluation in anticancer drug development.