nmr-based-fragment-screening-minimum-sample-but-maximum-automation

NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode

Fragment-based screening (FBS) is a well-validated and accepted concept within the drug discovery process both in academia and industry. The greatest ...

Johann Wolfgang Goethe-University Frankfurt

German Cancer Consortium (DKTK) and DKFZ

We report here the nuclear magnetic resonance  F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow-up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low-micromolar binding affinity without losing binding specificity between two different terminator structures.

A. Niesteruk

Institute for Organic Chemistry and Chemical Biology,
Center for Biomolecular Magnetic Resonance (BMRZ),
Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ)

Johann Wolfgang Goethe-University Frankfurt

NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode

A. Niesteruk

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Institute for Organic Chemistry and Chemical Biology,Center for Biomolecular Magnetic Resonance (BMRZ),Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ)

Johann Wolfgang Goethe-University Frankfurt

NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode

Institute for Organic Chemistry and Chemical Biology,
Center for Biomolecular Magnetic Resonance (BMRZ),
Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ)