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

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dc.contributor.advisor Böckler, Frank (Prof. Dr.)
dc.contributor.author Dammann, Marcel
dc.date.accessioned 2022-09-05T07:40:52Z
dc.date.available 2022-09-05T07:40:52Z
dc.date.issued 2023-10-01
dc.identifier.uri http://hdl.handle.net/10900/131430
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1314309 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-72788
dc.description.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. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en en
dc.subject.classification Pharmazie , Screening de_DE
dc.subject.ddc 500 de_DE
dc.subject.ddc 540 de_DE
dc.subject.ddc 610 de_DE
dc.subject.other Kinase en
dc.subject.other FBDD en
dc.subject.other NMR en
dc.subject.other ITC en
dc.subject.other Crystallography en
dc.title Experimental Evaluation of Halogen-Enriched Fragment Library Reveals Halogen Bonding in Multiple, Novel Binding Motifs en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2022-07-19
utue.publikation.fachbereich Pharmazie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.noppn yes de_DE


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