Rational Drug Design Dr Robert Sbaglia. Curriculum Vitae 1994-1998Bachelor of Science (Honours), University of Melbourne 1994-1998Bachelor of Science.

Rational Drug DesignRational Drug Design

Dr Robert SbagliaDr Robert Sbaglia

Curriculum VitaeCurriculum Vitae

1994-19981994-1998 Bachelor of Science (Honours), Bachelor of Science (Honours), University of MelbourneUniversity of Melbourne

1998-20021998-2002 Doctor of Philosophy, Centre for Doctor of Philosophy, Centre for Drug Design and Development Drug Design and Development (later IMB), University of (later IMB), University of Queensland – Queensland – Rheumatoid Rheumatoid ArthritisArthritis

20002000 University of Perugia, Italy – University of Perugia, Italy – Alzheimer’s DiseaseAlzheimer’s Disease

20032003 Postdoctoral Fellowship, Postdoctoral Fellowship, University of Florence, Italy - CancerUniversity of Florence, Italy - Cancer

Irrational Drug Design?Irrational Drug Design?

High Throughput Screening (HTS)High Throughput Screening (HTS)ExpensiveExpensiveSlowSlowHit and MissHit and Miss

Natural Products (eg Taxol)Natural Products (eg Taxol)Not easily synthesisedNot easily synthesisedNot easily modifiedNot easily modified

TaxolTaxol

Rational Drug DesignRational Drug Design

Medical ResearchersMedical ResearchersBiologistsBiologistsPharmacologistsPharmacologistsChemistsChemistsComputational chemistsComputational chemistsBioinformaticiansBioinformaticiansPharmacistsPharmacists

The ProcessThe ProcessIdentify disease

proteinIdentify active site

Determine structureof Protein

Virtual Screening ofDrug Candidates

Synthesis of LeadCompounds

PharmacologicalTesting

Optimisation Clinical Trials Drug

How Does Drug Design fit into How Does Drug Design fit into 2008 Chemistry?2008 Chemistry?

Unit 3, Area of Study 2, Outcome 2Unit 3, Area of Study 2, Outcome 2

structure and systematic nomenclature of alkanes, alkenes, amines, structure and systematic nomenclature of alkanes, alkenes, amines, chloroalkanes, alkanols and carboxylic acids up to C10;chloroalkanes, alkanols and carboxylic acids up to C10;

common reactions of organic compounds: addition reactions of common reactions of organic compounds: addition reactions of alkenes, substitution reactions of alkanes and primary chloroalkanes, alkenes, substitution reactions of alkanes and primary chloroalkanes, oxidation of primary alkanols, esterfication;oxidation of primary alkanols, esterfication;

organic reaction pathways including the production of esters from organic reaction pathways including the production of esters from alkenes, condensation and polymerisation reactions that produce alkenes, condensation and polymerisation reactions that produce large biomolecules;large biomolecules;

primary, secondary and tertiary structure of proteins and the function primary, secondary and tertiary structure of proteins and the function of protein catalysts (enzymes);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 DNAthe structure and bonding of DNA and its applications in forensic and its applications in forensic

analysis;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 function of organic molecules in the design and synthesis of

medicines including the production of aspirin from salicylic acid. medicines including the production of aspirin from salicylic acid.

How Does Drug Design fit into How Does Drug Design fit into 2008 Chemistry?2008 Chemistry?

Unit 3, Area of Study 1, Outcome 1Unit 3, Area of Study 1, Outcome 1

principles and applications of chromatographic principles and applications of chromatographic techniques and interpretation of qualitative and techniques and interpretation of qualitative and quantitative data from thin layer chromatography (TLC), quantitative data from thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and high performance liquid chromatography (HPLC) and gas chromatography (GC);gas chromatography (GC);

principles and applications of spectroscopic techniques principles and applications of spectroscopic techniques and interpretation of qualitative and quantitative data and interpretation of qualitative and quantitative data from atomic absorption spectroscopy (AAS), infrared from atomic absorption spectroscopy (AAS), infrared spectroscopy (IR), mass spectroscopy, spectroscopy (IR), mass spectroscopy, nuclear nuclear magnetic resonance spectroscopy (NMR)magnetic resonance spectroscopy (NMR), and visible , and visible and ultraviolet spectroscopy (visible-UV);and ultraviolet spectroscopy (visible-UV);

matching analytical technique/s to a particular task.matching analytical technique/s to a particular task.

Identification of Disease ProteinIdentification of Disease Protein

Identification of Disease ProteinIdentification of Disease Protein

Identify Active SiteIdentify Active Site

Mutagenesis studiesMutagenesis studiesExpress proteins with changes in amino acid Express proteins with changes in amino acid

sequencessequences Identify amino acids involved in functionIdentify amino acids involved in function

Identify Active SiteIdentify Active Site

Structure DeterminationStructure Determination

X-ray X-ray CrystallographyCrystallography

Nuclear Magnetic Nuclear Magnetic Resonance (NMR)Resonance (NMR)

Homology Homology ModellingModelling

Bovine Rhodopsin Crystal Bovine Rhodopsin Crystal StructureStructure

Structure DeterminationStructure Determination

C5a ReceptorC5a ReceptorGPCRGPCRMembrane BoundMembrane BoundHomology ModelHomology Model

Virtual ScreeningVirtual Screening

Known structures of organic compoundsKnown structures of organic compoundsLibraries of Virtual CompoundsLibraries of Virtual CompoundsPrograms calculate affinity for proteinPrograms calculate affinity for proteinNarrow down to small number of Narrow down to small number of

possiblitiespossiblities

Virtual ScreeningVirtual Screening

What makes a good drug?What makes a good drug?

Compounds can Compounds can interact throughinteract throughHydrophobic/Hydrophobic/

hydrophilic pocketshydrophilic pocketsChargeChargeHydrogen bondingHydrogen bonding

““Lock and Key”Lock and Key”

Virtual ScreeningVirtual Screening

HIV proteaseHIV protease

Synthesis, Testing and Synthesis, Testing and OptimisationOptimisation

Small changes to lead compoundsSmall changes to lead compoundsMust considerMust consider

SolubilitySolubilitySpecificitySpecificityBioavailablityBioavailablityToxicityToxicityCostCost

Synthesis, Testing and Synthesis, Testing and OptimisationOptimisation

TrialsTrials

Animal ModelAnimal ModelHuman TrialsHuman Trials

Phase 1 – 20-80 peoplePhase 1 – 20-80 peoplePhase 2 – 100-300 peoplePhase 2 – 100-300 peoplePhase 3 – 1,000 – 3,000 peoplePhase 3 – 1,000 – 3,000 peoplePhase 4 – post-marketing studiesPhase 4 – post-marketing studies