Therapeutic Path to Triple Knockout: Investigating the Pan-inhibitory Mechanisms of AKT, CDK9, and TNKS2 by a Novel 2-phenylquinazolinone Derivative in Cancer Therapy- An In-silico Investigation Therapy


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Background:Blocking the oncogenic Wnt//β-catenin pathway has of late been investigated as a viable therapeutic approach in the treatment of cancer. This involves the multi-targeting of certain members of the tankyrase-kinase family; Tankyrase 2 (TNKS2), Protein Kinase B (AKT), and Cyclin- Dependent Kinase 9 (CDK9), which propagate the oncogenic Wnt/β-catenin signalling pathway.

Methods:During a recent investigation, the pharmacological activity of 2-(4-aminophenyl)-7-chloro- 3H-quinazolin-4-one was repurposed to serve as a ‘triple-target’ inhibitor of TNKS2, AKT and CDK9. Yet, the molecular mechanism that surrounds its multi-targeting activity remains unanswered. As such, this study aims to explore the pan-inhibitory mechanism of 2-(4-aminophenyl)-7-chloro-3H-quinazolin- 4-one towards AKT, CDK9, and TNKS2, using in silico techniques.

Results:Results revealed favourable binding affinities of -34.17 kcal/mol, -28.74 kcal/mol, and -27.30 kcal/mol for 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one towards TNKS2, CDK9, and AKT, respectively. Pan-inhibitory binding of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one is illustrated by close interaction with specific residues on tankyrase-kinase. Structurally, 2-(4-aminophenyl)-7-chloro- 3H-quinazolin-4-one had an impact on the flexibility, solvent-accessible surface area, and stability of all three proteins, which was illustrated by numerous modifications observed in the unbound as well as the bound states of the structures, which evidenced the disruption of their biological function. Prediction of the pharmacokinetics and physicochemical properties of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4- one further established its inhibitory potential, evidenced by the favourable absorption, metabolism, excretion, and minimal toxicity properties.

Conclusion:The following structural insights provide a starting point for understanding the paninhibitory activity of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one. Determining the criticality of the interactions that exist between the pyrimidine ring and catalytic residues could offer insight into the structure-based design of innovative tankyrase-kinase inhibitors with enhanced therapeutic effects.

Sobre autores

Xylia Peters

Department of Pharmaceutical Science, University of KwaZulu-Natal

Email: info@benthamscience.net

Ghazi Elamin

Department of Pharmaceutical Science,, University of KwaZulu-Natal

Email: info@benthamscience.net

Aimen Aljoundi

Department of Pharmaceutical Science, University of KwaZulu-Natal

Email: info@benthamscience.net

Mohamed Alahmdi

Department of Pharmaceutical Science, University of Tabuk

Email: info@benthamscience.net

Nader Abo-Dya

Department of Pharmaceutical Science, Tabuk University

Email: info@benthamscience.net

Peter Sidhom

Department of Pharmacy,, Tanta University

Email: info@benthamscience.net

Ahmed Tawfeek

Chemistry Department, College of Science,, King Saud University

Email: info@benthamscience.net

Mahmoud Ibrahim

Department of Pharmaceutical Science,, University of KwaZulu-Natal

Email: info@benthamscience.net

Opeyemi Soremekun

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London

Email: info@benthamscience.net

Mahmoud Soliman

Department of Pharmaceutical Science, University of KwaZulu-Natal

Autor responsável pela correspondência
Email: info@benthamscience.net

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