The binding mechanism of NHWD-870 to bromodomain-containing protein 4 based on molecular dynamics simulations and free energy calculation

Abstract

Bromodomain and extra-terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers with tandem bromodomains. Small-molecule inhibitors of BET proteins are a promising treatment strategy against cancer. For example,...

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations

“…Hydrogen bonds formed between small chemical scaffolds of BET inhibitors and N140 (N433) of the acetylated lysine site of BRD4-BD1 (BRD4-BD2) are commonly required for binding of BET inhibitors. ,− Hydrogen bonding plays an important role in drug design. − In particular, it plays a significant role in competitive inhibitor binding to the active site of the bromodomain of BET proteins, including BRD4-BD1 and BRD4-BD2 (Figure ). In this study, the hydrogen bond was confirmed when the distance between the acceptor and donor atoms was less than 3.5 Å, and the internal angle of the acceptor···H-donor was above 120°.…”

“…A reliable inhibitor–protein complex structure plays a vital role in drug development. − Computational methods, such as homology modeling, − molecular docking, − molecular dynamics (MD) simulation, − binding free energy calculation, − and others − are widely employed. These methods were used to elucidate the binding models and mechanisms of inhibitor/BET systems. − Thus, MD simulations and binding free energy calculations were employed in the present study to elucidate the selective-BD2 mechanism for the pyrrolopyridone core compounds.…”

Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase

“…The calculated binding free energies presented in Table show that the nonpolar (i.e., hydrophobic) term plays the most important role in complex formation. Because the per-residue free energy decomposition strategy is known to enable analysis of the inhibitor–protein interactions, ,− the interaction energies between the various residues of FAK and VS-4718 were computed using the MM/GBSA decomposition protocol (Tables S5 and S6). As indicated by the obtained results, several hydrophobic residues possessed substantial subtotal binding free energies.…”

“…The MD simulations have become increasingly important in the context of understanding the interactions between receptors (e.g., proteins, enzymes, or cyclodextrins) and ligands (e.g., inhibitors, stabilizers, and supermolecules). ,,− Therefore, MD simulations were carried out to explore the binding between VS-4718 and the FAK protein. The initial VS-4718/FAK complex structures obtained from the docking model were used as the initial complex conformations for subsequent simulations.…”

“…We herein report a VS-4718/FAK binding model obtained through the use of molecular docking and all-atom MD simulations. More specifically, the binding free energies are also calculated using the molecular mechanics generalized Born surface area (MM/GBSA) method, which is a valuable and powerful method for carrying out binding free energy calculations. − In addition, the hot residues present in the VS-4718/FAK binding models, which are likely to alter the binding affinity of VS-4718 with FAK, are identified by analyzing the energy decomposition for each residue. Ultimately, our aim is to carry out simulations that will provide the binding mechanism for VS-4718 with FAK, in addition to useful information that will facilitate the development of innovative FAK inhibitors.…”