Unravelling the Mechanistic Role of Quinazolinone Pharmacophore in the Inhibitory Activity of Bis-quinazolinone Derivative on Tankyrase-1 in the Treatment of Colorectal Cancer (CRC) and Non-small Cell Lung Cancer (NSCLC): A Computational Approach

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 Δ G bind than IWR-1 from the thermodynamics analysis, revealing the better inhibitory activity of Cpd 5 compared to IWR-1. High involvement of solvation energy (Δ G sol ) and the van der Waals energy (Δ E vdW ) 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.