Rational Drug Design Dr Robert Sbaglia

Curriculum Vitae Bachelor of Science (Honours), University of Melbourne Bachelor of Science (Honours), University of Melbourne Doctor of Philosophy, Centre for Drug Design and Development (later IMB), University of Queensland – Rheumatoid Arthritis Doctor of Philosophy, Centre for Drug Design and Development (later IMB), University of Queensland – Rheumatoid Arthritis 2000University of Perugia, Italy – Alzheimer’s Disease 2000University of Perugia, Italy – Alzheimer’s Disease 2003Postdoctoral Fellowship, University of Florence, Italy - Cancer 2003Postdoctoral Fellowship, University of Florence, Italy - Cancer

Irrational Drug Design? High Throughput Screening (HTS) High Throughput Screening (HTS) Expensive Expensive Slow Slow Hit and Miss Hit and Miss Natural Products (eg Taxol) Natural Products (eg Taxol) Not easily synthesised Not easily synthesised Not easily modified Not easily modified

Taxol

Rational Drug Design Medical Researchers Medical Researchers Biologists Biologists Pharmacologists Pharmacologists Chemists Chemists Computational chemists Computational chemists Bioinformaticians Bioinformaticians Pharmacists Pharmacists

The Process Identify disease protein Identify active site Determine structure of Protein Virtual Screening of Drug Candidates Synthesis of Lead Compounds Pharmacological Testing OptimisationClinical TrialsDrug

How Does Drug Design fit into 2008 Chemistry? Unit 3, Area of Study 2, Outcome 2 structure and systematic nomenclature of alkanes, alkenes, amines, chloroalkanes, alkanols and carboxylic acids up to C10; structure and systematic nomenclature of alkanes, alkenes, amines, chloroalkanes, alkanols and carboxylic acids up to C10; common reactions of organic compounds: addition reactions of alkenes, substitution reactions of alkanes and primary chloroalkanes, oxidation of primary alkanols, esterfication; common reactions of organic compounds: addition reactions of alkenes, substitution reactions of alkanes and primary chloroalkanes, oxidation of primary alkanols, esterfication; organic reaction pathways including the production of esters from alkenes, condensation and polymerisation reactions that produce large biomolecules; organic reaction pathways including the production of esters from alkenes, condensation and polymerisation reactions that produce large biomolecules; primary, secondary and tertiary structure of proteins and the function of protein catalysts (enzymes); primary, secondary and tertiary structure of proteins and the function of protein catalysts (enzymes); biochemical fuels including fermentation of sugars to produce ethanol; biochemical fuels including fermentation of sugars to produce ethanol; the structure and bonding of DNA and its applications in forensic analysis; the structure and bonding of DNA and its applications in forensic analysis; use of proteins as markers for disease; use of proteins as markers for disease; function of organic molecules in the design and synthesis of medicines including the production of aspirin from salicylic acid. function of organic molecules in the design and synthesis of medicines including the production of aspirin from salicylic acid.

How Does Drug Design fit into 2008 Chemistry? Unit 3, Area of Study 1, Outcome 1 principles and applications of chromatographic techniques and interpretation of qualitative and quantitative data from thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and gas chromatography (GC); principles and applications of chromatographic techniques and interpretation of qualitative and quantitative data from thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and gas chromatography (GC); principles and applications of spectroscopic techniques and interpretation of qualitative and quantitative data from atomic absorption spectroscopy (AAS), infrared spectroscopy (IR), mass spectroscopy, nuclear magnetic resonance spectroscopy (NMR), and visible and ultraviolet spectroscopy (visible-UV); principles and applications of spectroscopic techniques and interpretation of qualitative and quantitative data from atomic absorption spectroscopy (AAS), infrared spectroscopy (IR), mass spectroscopy, nuclear magnetic resonance spectroscopy (NMR), and visible and ultraviolet spectroscopy (visible-UV); matching analytical technique/s to a particular task. matching analytical technique/s to a particular task.

Identification of Disease Protein

Identify Active Site Mutagenesis studies Mutagenesis studies Express proteins with changes in amino acid sequences Express proteins with changes in amino acid sequences Identify amino acids involved in function Identify amino acids involved in function

Identify Active Site

Structure Determination X-ray Crystallography X-ray Crystallography Nuclear Magnetic Resonance (NMR) Nuclear Magnetic Resonance (NMR) Homology Modelling Homology Modelling

Bovine Rhodopsin Crystal Structure

Structure Determination C5a Receptor C5a Receptor GPCR GPCR Membrane Bound Membrane Bound Homology Model Homology Model

Virtual Screening Known structures of organic compounds Known structures of organic compounds Libraries of Virtual Compounds Libraries of Virtual Compounds Programs calculate affinity for protein Programs calculate affinity for protein Narrow down to small number of possiblities Narrow down to small number of possiblities

Virtual Screening

What makes a good drug? Compounds can interact through Compounds can interact through Hydrophobic/hydro philic pockets Hydrophobic/hydro philic pockets Charge Charge Hydrogen bonding Hydrogen bonding “Lock and Key” “Lock and Key”

Virtual Screening

HIV protease

Synthesis, Testing and Optimisation Small changes to lead compounds Small changes to lead compounds Must consider Must consider Solubility Solubility Specificity Specificity Bioavailablity Bioavailablity Toxicity Toxicity Cost Cost

Synthesis, Testing and Optimisation

Trials Animal Model Animal Model Human Trials Human Trials Phase 1 – people Phase 1 – people Phase 2 – people Phase 2 – people Phase 3 – 1,000 – 3,000 people Phase 3 – 1,000 – 3,000 people Phase 4 – post-marketing studies Phase 4 – post-marketing studies