28 research outputs found
3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands
Histone-lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone-bromodomain interaction is of great importance. We have identified the 3,5 dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC50 values of <5 μM for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains
Global Engineering Network fuer mikroelektronische Anwendungen. GEN-Elektronik Abschlussbericht
Available from TIB Hannover: F00B398 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung und Forschung (BMBF), Bonn (Germany)DEGerman
Enhanced Ligand Sampling for Relative Protein–Ligand Binding Free Energy Calculations
Free
energy calculations are used to study how strongly potential
drug molecules interact with their target receptors. The accuracy
of these calculations depends on the accuracy of the molecular dynamics
(MD) force field as well as proper sampling of the major conformations
of each molecule. However, proper sampling of ligand conformations
can be difficult when there are large barriers separating the major
ligand conformations. An example of this is for ligands with an asymmetrically
substituted phenyl ring, where the presence of protein loops hinders
the proper sampling of the different ring conformations. These ring
conformations become more difficult to sample when the size of the
functional groups attached to the ring increases. The Adaptive Integration
Method (AIM) has been developed, which adaptively changes the alchemical
coupling parameter λ during the MD simulation so that conformations
sampled at one λ can aid sampling at the other λ values.
The Accelerated Adaptive Integration Method (AcclAIM) builds on AIM
by lowering potential barriers for specific degrees of freedom at
intermediate λ values. However, these methods may not work when
there are very large barriers separating the major ligand conformations.
In this work, we describe a modification to AIM that improves sampling
of the different ring conformations, even when there is a very large
barrier between them. This method combines AIM with conformational
Monte Carlo sampling, giving improved convergence of ring populations
and the resulting free energy. This method, called AIM/MC, is applied
to study the relative binding free energy for a pair of ligands that
bind to thrombin and a different pair of ligands that bind to aspartyl
protease β-APP cleaving enzyme 1 (BACE1). These protein–ligand
binding free energy calculations illustrate the improvements in conformational
sampling and the convergence of the free energy compared to both AIM
and AcclAIM