Journal Article

Induction of zinc conjugated with Doxorubicin for the prevention of aggregating β-catenin in the Wnt signaling pathway investigated through computational approaches

Srinivasadesikan, Venkatesan, Ramachandran, Balajee, Gebru, Goyitom Gebremedhn, Muthupandian, Saravanan, Rajagopal, Gomathi, Pandi, Boomi, Sundarraj, Rajamanikandan, Deivanayagam, Paradesi

2025

Overview

Canonical Wnt signaling plays a key role in tumor cell proliferation which correlates with the accumulation of β-catenin resulting inactivation of the network of targets such as GSK3β, Axin, CK1. Uncontrolled expression of β-catenin leads to different types of cancers and other diseases such as sarcoma and mesenchymal tumor formation. However, β-catenin is an attractive target for cervical cancer. In the present study, the compounds such as Doxorubicin and Zinc conjugated with Doxorubicin were screened against β-catenin using Molecular Docking, Molecular Dynamics Simulation, MM/GBSA, and DFT approaches to explore their insights. The study further demonstrated that the binding energy of Zn conjugated with Doxorubicin has shown -7.2 kcal/mol and Doxorubicin registers -5.9 kcal/mol against β-catenin. The disruption between the β-catenin/Tcf-4 complex was observed through the Zinc-Doxorubicin complex, both the proteins are separated about 12 Å. The Zn-Doxorubicin was stabilized with the hydrophobic residues such as Val349 of β-catenin and Phe21 of Tcf-4. The DFT analysis using the B3LYP/6-31g(d,p) method explores that Zn-doxorubicin in complex with the binding site residues has shown the HOMO-LUMO gap of 2.55 eV. The binding free energy calculations exhibit the Zn conjugated Doxorubicin favors in the study by showing ~ 3 kcal/mol difference with Doxorubicin. The Zn-conjugated Doxorubicin will be discussed in the context of cervical cancer with the hope of improving drug efficacy and reducing toxicities for the betterment of the patient’s quality of life.

• Publisher: Public Library of Science
• Subject: Apoptosis / beta Catenin - chemistry / beta Catenin - metabolism / Binding energy / Binding Sites / Biology and Life Sciences / Cancer / Cancer therapies / Cell cycle / Cell proliferation / Cervical cancer / Chemotherapy / Doxorubicin / Doxorubicin - chemistry / Doxorubicin - pharmacology / Drug resistance / Free energy / Human papillomavirus / Humans / Hydrophobicity / Kinases / Ligands / Medical prognosis / Medicine and Health Sciences / Metal oxides / Molecular docking / Molecular Docking Simulation / Molecular dynamics / Molecular Dynamics Simulation / Molecular orbitals / Physical Sciences / Protein Binding / Proteins / Quality of life / Research and Analysis Methods / Residues / Sarcoma / Side effects / Signal transduction / Tumors / Wnt protein / Wnt Signaling Pathway - drug effects / Zinc / Zinc - chemistry / Zinc - pharmacology / β-Catenin