Virtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain

Spiliotopoulos, Dimitrios; Zhu, Jian; Wamhoff, Eike‐Christian; Deerain, Nicholas; Marchand, Jean-Rémy; Aretz, Jonas; Caflisch, Amedeo

doi:10.1016/j.bmcl.2017.04.001

Cited by 26 publications

(34 citation statements)

References 41 publications

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“…Both hydrogen bonds are present in all crystal structures of BAZ2A/B reported in this work, as well as in those previously disclosed with the exception of the complex between BAZ2B and 6‐hydroxyindole in which the NH of the ligand replaces the water W1 (PDB ID: https://www.rcsb.org/structure/5E9I). The scatter plot in Figure a shows that the distance to the bridging water is shorter than the distance to the side chain of the conserved asparagine for all compounds (except for the acetylindole derivative 8 ) in agreement with previous reports . Interestingly, the hydrogen bond lengths can be clustered on the basis of the chemical class of the compounds independently of the bound bromodomain.…”

Section: Resultsmentioning

confidence: 99%

“…Compound 5 was the mosta ctive against the BAZ2A bromodomain in both assays with an IC 50 value of 88 mm and a K d of 17 mm.I th as been reported by severalg roupst hat the K d values measured by the BROMOscan assay are up to an order of magnitude more favorable than the IC 50 values obtained by AlphaScreen. [14][15][16][17] Overall, the substructure search resulted in five new crystal structures but only am odest improvement of affinity with respect to the original hit (from a K d of 51 mm for fragment 1 of Ref.…”

Section: Substructure Searchmentioning

confidence: 99%

“…ChemMedChem 2018ChemMedChem , 13,1479ChemMedChem -1487 www.chemmedchem.org 2018 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim distance to the bridging water is shorter than the distance to the side chain of the conserved asparaginef or all compounds (except fort he acetylindole derivative 8)i na greement with previousr eports. [14,19,20] Interestingly,t he hydrogenb ond lengths can be clustered on the basis of the chemical class of the compounds independently of the bound bromodomain. The distance to the structurally conserved water reflectst he degree of burial of the compounds (Figure 3b).…”

Section: Comparison Of Binding Modesmentioning

confidence: 99%

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Structural Analysis of Small‐Molecule Binding to the BAZ2A and BAZ2B Bromodomains

et al. 2018

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The bromodomain-containing protein BAZ2A is a validated target in prostate cancer research, whereas the function of its paralogue BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand engages in essentially identical interactions in the BAZ2A and BAZ2B bromodomains. In contrast, the rest of the molecule is partially solvent-exposed and adopts different orientations with different interactions in the two bromodomains. Some of these differences could be exploited for designing inhibitors with selectivity within the BAZ2 bromodomain subfamily.

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Section: Resultsmentioning

confidence: 99%

Section: Substructure Searchmentioning

confidence: 99%

Section: Comparison Of Binding Modesmentioning

confidence: 99%

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Structural Analysis of Small‐Molecule Binding to the BAZ2A and BAZ2B Bromodomains

et al. 2018

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“…Pioneering work by the Shoichet’s Lab in this area led to the conclusion that although virtual fragment screening is adequate, with hit rates of 14.5% [63] and correct pose prediction, it mostly finds low specificity molecules. The effectiveness of this method for screening and de novo design are well documented in the literature [64,65,66,67,68]. Docking is particularly well suited for fragment screening since the molecules used as fragments are small and not very flexible (less than three rotatable bonds).…”

Section: Small Ligands and Fragment Screeningmentioning

confidence: 99%

Solvents to Fragments to Drugs: MD Applications in Drug Design

et al. 2018

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Simulations of molecular dynamics (MD) are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: Binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals solvent structures and preferential interaction sites (hot spots) on the protein surface. The information provided by water and its cosolvents can be used very effectively to understand protein ligand recognition and to improve the predictive capability of well-established methods such as molecular docking. The application of MD simulations to the study of the association of proteins with drug-like compounds is currently only possible for specific cases, as it remains computationally very expensive and labor intensive. MDmix simulations on the other hand, can be used systematically to address some of the common tasks in SBDD. With the advent of new tools and faster computers we expect to see an increase in the application of mixed solvent MD simulations to a plethora of protein targets to identify new drug candidates.

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“…The effectiveness of this method for screening and de novo design are well documented in the literature. [55][56][57][58][59] Docking is particularly well suited for fragment screening since the molecules used as fragments are small and not very flexible (less than three rotatable bonds). Nevertheless, if the binding site is not known, it can lead to many false positives.…”

Section: Small Ligands and Fragment Screeningmentioning

confidence: 99%

Solvents to Fragments to Drugs: MD Applications in Drug Design

Defelipe¹,

Arcon²,

Modenutti³

et al. 2018

Preprint

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Molecular dynamics(MD) simulations are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals the solvent structure and preferential interaction sites (hot spots) on the protein surface. This information is largely transferable across all classes of protein ligands (from water to drugs) and can be used very effectively to understand ligand recognition and improve the predictive capability of well-established methods such as molecular docking. MD simulations for protein and drug or drug-like compounds are now being used but are still computationally expensive and can only be applied to specific cases. On the other hand, MDmix simulations can now be used in SBDD and we will describe the latest developments and implementations. We expect to see an increase in the application of these techniques to a plethora of protein targets to identify new drug candidates with the advent of new tools and faster computers.

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Virtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain

Cited by 26 publications

References 41 publications

Structural Analysis of Small‐Molecule Binding to the BAZ2A and BAZ2B Bromodomains

Structural Analysis of Small‐Molecule Binding to the BAZ2A and BAZ2B Bromodomains

Solvents to Fragments to Drugs: MD Applications in Drug Design

Solvents to Fragments to Drugs: MD Applications in Drug Design

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