Deciphering the crucial molecular properties of a series of Benzothiazole Hydrazone inhibitors that targets anti-apoptotic Bcl-xL protein

Abstract

The Bcl-2 family proteins are the central regulators of apoptosis. Due to its predominant role in cancer progression, the Bcl-2 family proteins act as attractive therapeutic targets. Recently, molecular series of Benzothiazole Hydrazone (BH) inhibitors that exhibits drug-likeness characteristics, which selectively targets Bcl-xL have been reported. In the present study, docking was used to explore the plausible binding mode of the highly active BH inhibitor with Bcl-xL; and Molecular Dynamics (MD) simulation was applied to investigate the stability of predicted conformation over time. Furthermore, the molecular properties of the series of BH inhibitors were extensively investigated by pharmacophore based 3D-QSAR model. The docking correctly predicted the binding mode of the inhibitor inside the Bcl-xL hydrophobic groove, whereas the MD-based free energy calculation exhibited the binding strength of the complex over the time period. Furthermore, the residue decomposition analysis revealed the major energy contributing residues - F105, L108, L130, N136, and R139 - involved in complex stability. Additionally, a six-featured pharmacophore model - AAADHR.89 - was developed using the series of BH inhibitors that exhibited high survival score. The statistically significant 3D-QSAR model exhibited high correlation co-efficient (R² = .9666) and cross validation co-efficient (Q² = .9015) values obtained from PLS regression analysis. The results obtained from the current investigation might provide valuable insights for rational drug design of Bcl-xL inhibitor synthesis.

Keywords: 3D-QSAR model; AAP: Anti-apoptotic protein; BH: Benzothiazole Hydrazone inhibitors; Bcl2: B-Cell lymphocytes; Benzothiazole Hydrazone inhibitors; CPH: Common Pharmacophore Hypothesis; EF: Enrichment Factor; MD: Molecular Dynamics Simulations; MM-PB/GBSA: Molecular Mechanics-Poisson Boltzmann/Generalized Born Solvent Accessibility; PAP: Pro-apoptotic peptides; PLS : Partial Least squared; QSAR: Quantitative Structure Activity Relationship; RIE: Robust Initial Enhancement; ROC: Receiver Operator Characteristics; anti-apoptotic proteins; binding free energy estimation; molecular dynamics simulations.