Deciphering Selectivity Mechanism of BRD9 and TAF1(2) toward Inhibitors Based on Multiple Short Molecular Dynamics Simulations and MM-GBSA Calculations

Abstract

BRD9 and TAF1(2) have been regarded as significant targets of drug design for clinically treating acute myeloid leukemia, malignancies, and inflammatory diseases. In this study, multiple short molecular dynamics simulations combined with the molecular mechanics generalized Born surface area method were employed to investigate the binding selectivity of three ligands, 67B, 67C, and 69G, to BRD9/TAF1(2) with IC50 values of 230/59 nM, 1400/46 nM, and 160/410 nM, respectively. The computed binding free energies from the MM-GBSA method displayed good correlations with that provided by the experimental data. The results indicate that the enthalpic contributions played a critical factor in the selectivity recognition of inhibitors toward BRD9 and TAF1(2), indicating that 67B and 67C could more favorably bind to TAF1(2) than BRD9, while 69G had better selectivity toward BRD9 over TAF1(2). In addition, the residue-based free energy decomposition approach was adopted to calculate the inhibitor–residue interaction spectrum, and the results determined the gatekeeper (Y106 in BRD9 and Y1589 in TAF1(2)) and lipophilic shelf (G43, F44, and F45 in BRD9 and W1526, P1527, and F1528 in TAF1(2)), which could be identified as hotspots for designing efficient selective inhibitors toward BRD9 and TAF1(2). This work is also expected to provide significant theoretical guidance and insightful molecular mechanisms for the rational designs of efficient selective inhibitors targeting BRD9 and TAF1(2).

Binding Mechanism of Inhibitors to BRD4 and BRD9 Decoded by Multiple Independent Molecular Dynamics Simulations and Deep Learning

“…Wang et al conducted multiple short MD simulations to study the binding selectivity of inhibitors to BRD9 and TAF1 (2). Their work revealed that enthalpy contributions play a critical role in the selective recognition of inhibitors towards BRD9 and TAF1(2) [39]. Considering the important roles of BRD4 and BRD9 in diseases, it is necessary to explore the molecular mechanisms underlying the binding selectivity of inhibitors to BRD4 and BRD9 in order to develop highly selective inhibitors targeting BRDs.…”

Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies

“…Multiple computational technologies, such as molecular dynamics (MD) simulations [ 25 , 26 , 27 , 28 , 29 , 30 ], calculations of binding free energies [ 31 , 32 , 33 , 34 ], principal component analysis, (PCA) [ 35 , 36 , 37 , 38 ] etc., play significant roles in investigating the atomic-level mechanism of binding between inhibitors and targets. Conventional MD simulations (cMD) are usually used to obtain conformational samplings of inhibitor–target complexes, but multiple separate MD (MSMD) simulations recently adopted by different work groups can reasonably improve the sampling efficiency of conformations [ 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. Binding free energy calculations are applied to evaluate the binding ability and modes of inhibitors to targets, which are involved in molecular mechanics Poisson–Boltzmann/generalized Born surface area (MM-PB/GBSA) [ 46 , 47 , 48 ], solvated interaction energy (SIE) [ 49 ], thermodynamic integration (TI) [ 50 , 51 , 52 ] and free energy perturbation (FEP) [ 53 , 54 , 55 , 56 ].…”