Structure-based virtual screening of novel, high-affinity BRD4 inhibitors

Muvva, Charuvaka; Singam, Ettayapuram Ramaprasad Azhagiya; Raman, Srivatsan; Subramanian, V.

doi:10.1039/c4mb00243a

Cited by 34 publications

(23 citation statements)

References 41 publications

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“…In an independent effort, cellular high-throughput screening aiming at the identification of modulators of the ApoA1 pathway was performed [11,[88][89][90]. Later, virtual screening and fragment-based drug discovery have been reported to successfully deliver novel BET inhibitors [91][92][93][94]. Among the most popular methods used in biochemical assays are AlphaScreen ® (PerkinElmer), fluorescence polarization, time-resolved fluorescence resonance energy transfer and the BROMOscan SM technology (DiscoveRx) [95][96][97].…”

Section: Discovery Approachesmentioning

confidence: 99%

Targeting BET Bromodomains for Cancer Treatment

et al. 2015

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The bromodomain and extraterminal (BET) subfamily of bromodomain-containing proteins has emerged in the last few years as an exciting, novel target group. BRD4, the best studied BET protein, is implicated in a number of hematological and solid tumors. This is linked to its role in modulating transcription elongation of essential genes involved in cell cycle and apoptosis such as c-Myc and BCL2. Potent BET inhibitors with promising antitumor efficacy in a number of preclinical cancer models have been identified in recent years. This led to clinical studies focusing mostly on the treatment of leukemia and lymphoma, and first encouraging signs of efficacy have already been reported. Here we discuss the biology of BRD4, its known interaction partners and implication in different tumor types. Further, we summarize the current knowledge on BET bromodomain inhibitors.

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Section: Discovery Approachesmentioning

confidence: 99%

Targeting BET Bromodomains for Cancer Treatment

et al. 2015

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“…), are the only interaction modules that specifically recognize acetylated lysine residues of histones during transcriptional activation. [14][15][16][17][18] Many of BRDs are regulators of gene transcription such as histone acetyltransferases, components of chromatin remodeling complexes, and methyltransferases. 16,19 Human proteome analysis has revealed that there are eight distinct BRD families, representing 61 different BRDs from 46 separate proteins, although others may still be undiscovered.…”

Section: Introductionmentioning

confidence: 99%

Binding Kinetics versus Affinities in BRD4 Inhibition

Zhou

Wang

Liu

et al. 2015

J. Chem. Inf. Model.

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Bromodomains (BRDs) are protein modules that selectively recognize histones as a "reader" by binding to an acetylated lysine substrate. The human BRD4 has emerged as a promising drug target for a number of disease pathways, and several potent BRD inhibitors have been discovered experimentally recently. However, the detailed inhibition mechanism especially for the inhibitor binding kinetics is not clear. Herein, by employing classical molecular dynamics (MD) and state-of-the-art density functional QM/MM MD simulations, the dynamic characteristics of ZA-loop in BRD4 are revealed. And then the correlation between binding pocket size and ZA-loop motion is elucidated. Moreover, our simulations found that the compound (-)-JQ1 could be accommodated reasonably in thermodynamics whereas it is infeasible in binding kinetics against BRD4. Its racemate (+)-JQ1 proved to be both thermodynamically reasonable and kinetically achievable against BRD4, which could explain the previous experimental results that (+)-JQ1 shows a high inhibitory effect toward BRD4 (IC50 is 77 nM) while (-)-JQ1 is inactive (>10 μM). Furthermore, the L92/L94/Y97 in the ZA-loop and Asn140 in the BC-loop are identified to be critical residues in (+)-JQ1 binding/releasing kinetics. All these findings shed light on further selective inhibitor design toward BRD family, by exploiting the non-negligible ligand binding kinetics features and flexible ZA-loop motions of BRD, instead of only the static ligand-protein binding affinity.

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“…27 This protein is particularly suitable for this type of calculation, since the ligands bind near its surface and with clear access to the solvent, avoiding steric clashes during the pulling process. It is worth noting that the first BRD4 bromodomain has already been the target of numerous computational studies on ligand binding, using a range of methods such as fragment-based docking, 33 the MM-PBSA/GBSA method combined with steered molecular dynamics (SMD), 34 and free energy techniques, such as umbrella sampling, 35 ABF, 21 and alchemical methods. 11 In this last study, Aldeghi et al computed the binding free energies of several molecules to the BRD4 bromodomain, starting both from the crystal structure complexes and the binding poses obtained after performing protein–ligand rigid docking, and obtained encouraging agreement with experiment.…”

Section: Introductionmentioning

confidence: 99%

Attach-Pull-Release Calculations of Ligand Binding and Conformational Changes on the First BRD4 Bromodomain

Heinzelmann

Henriksen

Gilson

2017

J. Chem. Theory Comput.

122

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Bromodomains, protein domains involved in epigenetic regulation, are able to bind small molecules with high affinity. In the present study, we report free energy calculations for the binding of seven ligands to the first BRD4 bromodomain, using the attach-pull-release (APR) method to compute the reversible work of removing the ligands from the binding site and then allowing the protein to relax conformationally. We test three different water models, TIP3P, TIP4PEw, and SPC/E, as well as the GAFF and GAFF2 parameter sets for the ligands. Our simulations show that the apo crystal structure of BRD4 is only metastable, with a structural transition happening in the absence of the ligand typically after 20 ns of simulation. We compute the free energy change for this transition with a separate APR calculation on the free protein and include its contribution to the ligand binding free energies, which generally causes an underestimation of the affinities. By testing different water models and ligand parameters, we are also able to assess their influence in our results and determine which one produces the best agreement with the experimental data. Both free energies associated with the conformational change and ligand binding are affected by the choice of water model, with the two sets of ligand parameters affecting their binding free energies to a lesser degree. Across all six combinations of water model and ligand potential function, the Pearson correlation coefficients between calculated and experimental binding free energies range from 0.55 to 0.83, and the root-mean-square errors range from 1.4–3.2 kcal/mol. The current protocol also yields encouraging preliminary results when used to assess the relative stability of ligand poses generated by docking or other methods, as illustrated for two different ligands. Our method takes advantage of the high performance provided by graphics processing units and can readily be applied to other ligands as well as other protein systems.

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Structure-based virtual screening of novel, high-affinity BRD4 inhibitors

Cited by 34 publications

References 41 publications

Targeting BET Bromodomains for Cancer Treatment

Targeting BET Bromodomains for Cancer Treatment

Binding Kinetics versus Affinities in BRD4 Inhibition

Attach-Pull-Release Calculations of Ligand Binding and Conformational Changes on the First BRD4 Bromodomain

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