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:

• anti-apoptotic proteins
• Benzothiazole Hydrazone inhibitors
• molecular dynamics simulations
• binding free energy estimation
• 3D-QSAR model

Abbreviations:

• Bcl2: B-Cell lymphocytes
• BH: Benzothiazole Hydrazone inhibitors
• MD: Molecular Dynamics Simulations
• QSAR: Quantitative Structure Activity Relationship
• PLS : Partial Least squared
• AAP: Anti-apoptotic protein
• PAP: Pro-apoptotic peptides
• MM-PB/GBSA: Molecular Mechanics-Poisson Boltzmann/Generalized Born Solvent Accessibility
• EF: Enrichment Factor
• RIE: Robust Initial Enhancement
• ROC: Receiver Operator Characteristics
• CPH: Common Pharmacophore Hypothesis

Acknowledgments

MP gratefully acknowledge the use of bioinformatics infrastructure facility supported by Biocenter Finland; CSC-IT Center for Science [project number AA1268] and [project number 2000461] for computational facility; Dr Jukka Lehtonen for the IT support; Dr. Sabarinathan Radhakrishnan, Institute for Research in Biomedicine, Barcelona, Spain, for the MD analysis script; and special thanks to Prof. Mark Johnson, Åbo Akademi University for providing the lab facility.