Experimental Evaluation of Halogen-Enriched Fragment Library Reveals Halogen Bonding in Multiple, Novel Binding Motifs

DSpace Repository


Dateien:

URI: http://hdl.handle.net/10900/131430
http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1314309
http://dx.doi.org/10.15496/publikation-72788
Dokumentart: Dissertation
Date: 2023-10-01
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Pharmazie
Advisor: Böckler, Frank (Prof. Dr.)
Day of Oral Examination: 2022-07-19
DDC Classifikation: 500 - Natural sciences and mathematics
540 - Chemistry and allied sciences
610 - Medicine and health
Keywords: Pharmazie , Screening
Other Keywords:
Kinase
FBDD
NMR
ITC
Crystallography
License: Publishing license including print on demand
Order a printed copy: Print-on-Demand
Show full item record

Inhaltszusammenfassung:

Die Dissertation ist gesperrt bis zum 01. Oktober 2023 !

Abstract:

Fragment-based drug discovery is a standard method for generating new starting points for pharmacologically active substances. The in-house designed library (HEFLib) includes halogenated fragments capable of forming distinctive interaction patterns. The screening of eight proteins (AAK1, BIRC5, CAMK1g, DOT1L, DYRK1a, IDO1, JNK2/3) via STD-NMR showed various hit rates. Statistical analysis of the screenings revealed the first indication of a significant occurrence of halogen bonds. The most promising hits were prioritized by multiple characteristics and validated by ITC measurements. Out of the more than 1500 STD results, over 300 fragment protein pairs were measured in the ITC, and 25 fragments could be verified as micromolar binders. Many verified hits could function as starting points for further development, as they feature outstanding ligand efficiency and are highly soluble. Around three fragments, a more sophisticated evaluation was carried out, and analogs were measured to elucidate structure affinity relationships. In all three cases, the influence of the halogen was predominant. The exchange of bromine for iodine could further increase the preference and affinity of a fragment binding to JNK2 and JNK3. Moreover, the crystal structures of two different proteins with fragments revealed novel binding modes involving halogen bonds. In summary, the study proved the feasibility of detecting uncommon binding modes with the diversity-optimized halogen enriched fragment library (HEFLib). The results showcase the influence of halogens on binding modes and enlarge the scope of halogen bond application in medicinal chemistry.

This item appears in the following Collection(s)