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2. DRUG TARGETS. 0. TARGET SELECTIVITY. Between species Antibacterial and antiviral agents Identify targets which are unique to the invading pathogen Identify targets which are shared but which are significantly different in structure Within the body
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2. DRUG TARGETS 0 TARGET SELECTIVITY • Between species • Antibacterial and antiviral agents • Identify targets which are unique to the invading pathogen • Identify targets which are shared but which are significantly different in structure • Within the body • Selectivity between different enzymes, receptors etc. • Selectivity between receptor types and subtypes • Selectivity between isozymes • Organ selectivity
3.2.2 Testing with Receptors 0 • Not easy to isolate membrane bound receptors • Carried out on whole cells, tissue cultures, or isolated organs • Affinity - strength with which compounds bind to a receptor • Efficacy - measure of maximum biochemical effect resulting from binding of a compound to a receptor. • Potency - concentration of an agonist required to produce 50% of the maximum possible effect.
4.3 Lead Compounds from the Natural World 0 PLANT EXTRACTS • OPIUM- Morphine • CINCHONA BARK- Quinine • YEW TREE- Taxol
4.3 Lead Compounds from the Natural World 0 PLANT EXTRACTS WILLOW TREE - SALICYLIC ACID Aspirin COCA BUSH - COCAINE Procaine
4.3 Lead Compounds from the Natural World 0 VENOMS AND TOXINS Teprotide Captopril (anti-hypertensive)
Agonist Agonist 4.3 Lead Compounds from the Natural World 0 ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS
Antagonist Antagonist 4.3 Lead Compounds from the Natural World 0 ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS
4.4 Lead Compounds from the Synthetic World 0 PRONTOSIL
4.4 Lead Compounds from the Synthetic World 0 SULFANILAMIDE
4.4 Lead Compounds from the Synthetic World 0 RUBBER INDUSTRY ANTABUSE
4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS AUTOMATED SYNTHETIC MACHINES
AMINO ACID RESIN BEAD AMINO ACIDS X PEPTIDE 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - PEPTIDE SYNTHESIS
Y CHR1R2 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS RESIN BEAD N N O
R2 R3 H RESIN BEAD 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS N N O
R2 R3 R4 R5 RESIN BEAD 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS N N O EtO O
R2 R3 R4 R5 RESIN BEAD 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS N N N HN O
Y R2 R3 R4 R5 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS RESIN BEAD N N N HN O
Targets Lead compounds 4.5 Lead Compounds - Impact of the human genome project 0 The Past Lead Compound The Future Targets
4.6 Lead Compounds - de novo design X-RAY CRYSTALLOGRAPHY
4.6 Lead Compounds - de novo design PROTEIN STRUCTURE
4.6 Lead Compounds - de novo design Receptor
Scaffold CH3 + O Scaffold H3N Scaffold Scaffold Scaffold HO H-BOND CO2- IONIC BOND VDW BOND
HN NH N O O O S N N N O S O N O H2N 4.6 Lead Compounds - de novo design THYMIDYLATE KINASE INHIBITOR LEAD COMPOUND Optimisation ANTICANCER AGENT
4.7 Design of Lead Compounds using NMR Spectroscopy 0 NMR SPECTROSCOPY
4.7 Design of Lead Compounds using NMR Spectroscopy 0 Binding Site Protein
4.7 Design of Lead Compounds using NMR Spectroscopy 0 Protein NO OBSERVABLE BIOLOGICAL EFFECT
CH3 CH CH CH3 CH2 CH2 CH C C 4.7 Design of Lead Compounds using NMR Spectroscopy 0 13C NMR
4.7 Design of Lead Compounds using NMR Spectroscopy 0 CH3 CH CH CH3 CH2 CH2 CH C C 13C NMR
4.7 Design of Lead Compounds using NMR Spectroscopy 0 Protein Optimise epitope
4.7 Design of Lead Compounds using NMR Spectroscopy 0 Protein Optimise epitope Optimise epitope
4.7 Design of Lead Compounds using NMR Spectroscopy 0 Link Protein Optimise epitope Optimise epitope
4.7 Design of Lead Compounds using NMR Spectroscopy 0 LEAD COMPOUND
Me 4.7 Design of Lead Compounds using NMR Spectroscopy 0 Design of a lead compound as an immunosuppressant Epitope B Epitope A
Me 4.7 Design of Lead Compounds using NMR Spectroscopy 0 Design of a lead compound as an immunosuppressant Lead compound
