Journal of Angiotherapy
Integrative Biomedical Research (Journal of Angiotherapy) | Online ISSN  3068-6326
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Journal of Angiotherapy

Volume 6 Number 2 2022

Article Contents

RESEARCH ARTICLE   (Open Access)
Contents Vol 6 (2)

Structural and Pharmacological Insights into Withaferin a Binding to Mutant p53 (R248Q): Multi-Faceted Inhibitor in Cancer Treatment

Most Farhana Akter1*, Md. Robiul Islam1, Amena Khatun Manica2, Md Abu Bakar Siddique3, Tufael4

+ Author Affiliations

Journal of Angiotherapy 6 (2) 1-11 https://doi.org/10.25163/angiotherapy.6210432

Submitted: 22 August 2022 Revised: 07 October 2022  Published: 12 October 2022 

Abstract

Background: Mutations in the TP53 gene, particularly at codon 248 (R248Q), are frequently observed in aggressive tumors and correlate with poor prognosis. Therapeutic reactivation of mutant p53 remains a significant challenge in oncology.

Aim: This study aimed to evaluate and compare the binding behavior, drug-likeness, and toxicity profiles of APR-246-a clinically studied p53 reactivator-and Withaferin A-a natural compound with reported anticancer activity-against the R248Q mutant of p53.

Methods: The wild-type p53 structure (PDB ID: 2OCJ) was modified in silico to generate the R248Q mutant. Ligands were prepared and docked using AutoDock Vina via PyRx, targeting the DNA-binding domain. Interactions were visualized through BIOVIA Discovery Studio. ADMET properties and pharmacokinetics were predicted using SwissADME, while toxicity was assessed via the ProTox-II platform. Protein flexibility was evaluated using Normal Mode Analysis (NMA), comparing predicted B-factors with crystallographic data.

Results: Withaferin A demonstrated a stronger binding affinity and more extensive hydrogen bonding near the mutation site than APR-246. Both compounds satisfied Lipinski’s Rule and showed favorable gastrointestinal absorption. However, APR-246 displayed higher water solubility, while Withaferin A exhibited greater lipophilicity and lower predicted systemic toxicity. NMA confirmed structural flexibility near binding regions, supporting ligand accommodation.

Conclusion: Withaferin A shows promise as a natural alternative to APR-246 for targeting mutant p53. While computational results are encouraging, further validation through molecular dynamics simulations and biological assays is warranted to confirm therapeutic potential.

Keywords: Mutant p53 (R248Q), APR-246, Withaferin A, Molecular docking, In silico drug discovery.

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