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Drug Target Structure

Drug Target Structure. Physical methods of structure determination. Drug Targets (1). Biomolecular Drug Target Receptor Enzyme Transcription Factor Antigen Gene sequence. Drug Type agonist / antagonist enzyme inhibitor covalent / non-covalent Antibody

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Drug Target Structure

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  1. Drug Target Structure • Physical methods of structure determination l2PHA406 - Drug Design

  2. Drug Targets (1) • Biomolecular Drug Target • Receptor • Enzyme • Transcription Factor • Antigen • Gene sequence • Drug Type • agonist / antagonist • enzyme inhibitor • covalent / non-covalent • Antibody • anti-sense oligonucleotide l2PHA406 - Drug Design

  3. Biomolecular Drug Target • Receptor, Enzyme, Transcription Factor, Antigen, • Gene sequence • Techniques for drug target structure determination • Atomic resolution x-ray diffraction ( 1.5-3.0Å) • Neutron diffraction (~ 1.5-3.0Å) • NMR (1H,15N, 31P and 13C) (~ 5.0Å) • Atomic Force Microscopy (AFM) (~ 10-100Å) • Electron microscopy (often cryogenic) ( ~ 5.0Å) Target physical attributes - methodology, resolution (2) l2PHA406 - Drug Design

  4. X-ray co-ordinates for the complex between the enzyme HIV-1 protease and Amprenavir Structural method - X-ray diffraction (3) l2PHA406 - Drug Design

  5. NMR ensemble of BLK SH2 domain (a tyrosine kinase anti-cancer target comprising 20 structures, distance geometry solutions of NOE, nuclear overhauser enhancement experiments) Structural method - Nuclear Magnetic Resonance (4) l2PHA406 - Drug Design

  6. Structural method - Atomic Force Microscopy (5) A membrane protein from E.coli (a porin controlling osmotic environment) (a) High resolution topograph of the perisplasmic surface of 2-D OmpF porin crystals. The average shown was calculated from 25 translationally aligned subframes. To allow comparison, the electron density based on the X-ray structure of the OmpF trimer was rendered at a lateral resolution of 15Å. Zebra-like contours (dark and light blue) on the overlaid transparent AFM topograph mark zones of identical altitude, with a height difference between contours of 1Å. (b) Atomic model of protein-protein and lipid-protein interactions based on the X-ray structure of the porin trimer (from http://www.mih.unibas.ch/Booklet/Booklet96/Chapter3/Chapter3.html) l2PHA406 - Drug Design

  7. Structural method - Cryo-electron microscopy (6) A bacterial ‘molecular chaperone’ complex (GroEL-GroES) which is ATP dependent changes it state. The apical chains interact with other proteins undergoing protein folding duration ‘maturation’ on being released from their synthetic apparatus. l2PHA406 - Drug Design

  8. Structural method - Cryo-electron microscopy (7) 9Å resolution of the nicotinic acetylcholine receptor in a pore open (white) and pore closed state (blue). Ionic conduction occurs when the pore is open. l2PHA406 - Drug Design

  9. Fatty Acid Synthetase - bacterial Structural method - Cryo-electron microscopy (8) l2PHA406 - Drug Design

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