Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.653541
Title: Immunophilin ligand design
Author: Kontopidis, George A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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Abstract:
The general aim of the project is predict and select small molecule ligands which may bind to 3D protein templates. Proteins from the Immunophilin family were used. The putative ligands were selected by two different methods, by structure similarity and using the docking program LIDAEUS, which was developed in house by Dr. P. Taylor. Twenty nine small molecules were selected from a small molecule database and were tested with a fluorescence assay, a PPIase assay and x-ray crystallography for binding activity. Six new ligands have been discovered which bind to Cyp-A. In this work the IC50 (concentration in which half inhibition occurred) of the putative ligands were determined by rotamase inhibition assay. In addition the binding of the ligands was also confirmed by crystallographic experiments. The X-ray structures of 3-acetyl-1 methyl piperidine, ethyl-piperidine glyoxylate, dimethyl sulfoxide, tetramethylene sulfoxide, cyclopentanone and 5,5-dimethyl-1,3-cyclohexanedione bound to Cyp-A have been solved and refined with Rfactor for each structure less than 20%. The structural analysis of the native and ligand structures revealed a hydrophobic pocket surrounded by residues Asn 102, Met 61, Arg 55 and His 122, a hydrogen bond donor site of the main chain nitrogen Asn 102, and another hydrogen bond donor site of the guanidinium of Arg 55. The six novel ligands have been classified into 3 different families of compounds, 3-Acetyl-1 methyl piperidine and ethyl-piperidine glyoxylate belong to the piperidine family and share structural similarities with a natural substrate of Cyp-A the dipeptide Ala-Pro. Dimethyl sulfoxide (DMSO), tetramethylene sulfoxide and cyclopentanone form the DMSO family and they do not share any similarities with known Cyp-A ligand. Only one compound has been discovered in the third family. This compound 5,5-dimethyl-1,3-cyclohexanedione also known as dimedone shows some structural similarities with the Val 11 residue of the Cyp-A ligand cyclosporin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.653541  DOI: Not available
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