Bromodomains (BRDs)
are epigenetic interaction domains currently
recognized as emerging drug targets for development of anticancer
or anti-inflammatory agents. In this study, development of a selective
ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to
switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes
is presented. A compound collection was evaluated by consensus virtual
screening and a hit was identified. The biophysical study of protein–ligand
interactions was performed using X-ray crystallography and isothermal
titration calorimetry. Collective data supported the hypothesis that
affinity improvement could be achieved by enhancing interactions of
the complex with the solvent. The derived SAR along with free energy
calculations and a consensus hydration analysis using WaterMap and
SZmap algorithms guided rational design of a set of novel analogues.
The most potent analogue demonstrated high affinity of 3.3 μM
and an excellent selectivity profile, thus comprising a promising
lead for the development of chemical probes targeting PB1(5).
The “smart” amine donors o‐xylylenediamine and cadaverine were employed for the rapid screening of a large ketone library and subsequent preparative‐scale synthesis of selected compounds using a commercially available amine transaminase, ATA256. The methodology enables both screening and preparative‐scale biotransformations to be performed with a single enzyme and simplifies the generation of sp3‐rich small‐molecule libraries.
The development and application of a self-sufficient whole-cell system for transaminase biotransformations is described. The system relies on an engineered strain of Corynebacterium glutamicum that produces smart amine donors.
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