Abstract |
In recent years, tankyrase inhibition has gained a great focus as an anti- cancer strategy due to their modulatory effect on WNT/β- catenin pathway implicated in many malignancies, including colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). Based on the structural homology in the catalytic domain of PARP enzymes, bis- quinazolinone 5 (Cpd 5) was designed to be a potent selective tankyrase inhibitor. In this study, we employed molecular dynamics simulations and binding energy analysis to decipher the underlying mechanism of TNK-1 inhibition by Cpd 5 in comparison with a known selective tankyrase, IWR-1. The Cpd 5 had a relatively higher ΔGbind than IWR-1 from the thermodynamics analysis, revealing the better inhibitory activity of Cpd 5 compared to IWR-1. High involvement of solvation energy (ΔGsol) and the van der Waals energy (ΔEvdW) potentiated the affinity of Cpd 5 at TNK-1 active site. Interestingly, the keto group and the N3 atom of the quinazolinone nucleus of Cpd 5, occupying the NAM subsite, was able to form H-bond with Gly1185, thereby favoring the better stability and higher inhibitory efficacy of Cpd 5 relative to IWR-1. Our analysis proved that the firm binding of Cpd 5 was achieved by the quinazolinone groups via the hydrophobic interactions with the side chains of key site residues at the two subsite regions: His1201, Phe1188, Ala1191, and Ile1192 at the AD subsite and Tyr1224, Tyr1213, and Ala1215 at the NAM subsite. Thus, Cpd 5 is dominantly bound through π-π stacked interactions and other hydrophobic interactions. We believe that findings from this study would provide an important rationale towards the structure-based design of improved selective tankyrase inhibitors in cancer therapy.
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Authors | Felix O Okunlola, Oluwole B Akawa, Temitayo I Subair, Kehinde F Omolabi, Mahmoud E S Soliman |
Journal | Cell biochemistry and biophysics
(Cell Biochem Biophys)
Vol. 80
Issue 1
Pg. 1-10
(Mar 2022)
ISSN: 1559-0283 [Electronic] United States |
PMID | 34453681
(Publication Type: Journal Article)
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Copyright | © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. |
Chemical References |
- Enzyme Inhibitors
- Quinazolinones
- Tankyrases
|
Topics |
- Carcinoma, Non-Small-Cell Lung
(drug therapy)
- Colorectal Neoplasms
(drug therapy)
- Enzyme Inhibitors
(pharmacology)
- Humans
- Lung Neoplasms
(drug therapy)
- Quinazolinones
(pharmacology)
- Tankyrases
(antagonists & inhibitors, metabolism)
- Wnt Signaling Pathway
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