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 (R = .9666) and cross validation co-efficient (Q = .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.

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes

“…Previously, several studies have been carried out on different Bcl-2 family proteins using various MD simulation approaches. These investigations revealed (i) the driving force behind the intra-molecular conformational change [ 58 ], (ii) the helix stability [ 59 , 60 ], (iii) crucial residues involved in heterodimerization [ 61 ] (iv) crucial molecular properties responsible for complexity [ 62 , 63 , 64 ] (v) hot-spot residues [ 65 ] (vi) effects of Bim mutants [ 66 ] and (vii) the inter-helical interactions across families [ 67 ]. Based on this information, we attempted to explore the mMcl1—PAP complexes to extend our understanding of the molecular mechanism of heterodimerization by identifying the key features.…”

Identification of Ligand‐binding Hotspot Residues of CDK4 Using Molecular Docking and Molecular Dynamics Simulation

“…The total charge of the system was neutralized by adding three sodium ions. Subsequently, energy minimization was carried out followed by 1 ns of step by‐step equilibration of the system at constant temperature of 300 K . Long‐range electrostatics were computed using the Particle‐Mesh Ewald (PME) approach .…”

Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1

“…In our previous investigation, MD simulation was widely applied to Bcl-2 family proteins to gain an understanding on the mechanism of action [37,39,40,56]. Likewise, the current study is an attempt to extend our understanding of the molecular mechanism of Mcl1 with the highly active compound from the dataset-C40-used to construct the 3D-QSAR model.…”

“…The phase module [44] available in the Schrödinger 2016-3 suite provided an excellent tool for the construction of pharmacophore-based 3D-QSAR models in our previous studies [37,38,40], and thus the same method is adopted in the current investigation. Initially, all the low-energy conformers were imported to the "Develop Common Pharmacophore Hypotheses" panel, together with its activity values (3.975 to 7.509-pK i (µM)).…”

“…Taking advantage of this, the current study is an attempt to understand the mechanistic behavior of the current compound series with Mcl1. To achieve this, a combination of in silico approaches-pharmacophore-based 3D-Quantitative Structure Activity Relationship, docking, and Molecular Dynamics (MD) simulation-is widely used [34][35][36][37][38][39][40]. Correspondingly, a pharmacophore-based 3D-QSAR model was constructed based on known inhibitors obtained from the literature [33], with the aim of gaining knowledge on the critical chemical features responsible for its maximum activity.…”