1 © 2. DRUG TARGETS Between species Antibacterial and antiviral agentsAntibacterial and antiviral agents Identify targets which are unique to the invading pathogenIdentify targets which are unique to the invading pathogen Identify targets which are shared but which are significantly different in structureIdentify targets which are shared but which are significantly different in structure Within the body Selectivity between different enzymes, receptors etc.Selectivity between different enzymes, receptors etc. Selectivity between receptor types and subtypesSelectivity between receptor types and subtypes Selectivity between isozymesSelectivity between isozymes Organ selectivityOrgan selectivity TARGET SELECTIVITY

1 © Not easy to isolate membrane bound receptorsNot easy to isolate membrane bound receptors Carried out on whole cells, tissue cultures, or isolated organsCarried out on whole cells, tissue cultures, or isolated organs Affinity - strength with which compounds bind to a receptorAffinity - strength with which compounds bind to a receptor Efficacy - measure of maximum biochemical effect resulting from binding of a compound 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.Potency - concentration of an agonist required to produce 50% of the maximum possible effect Testing with Receptors

1 © 4.3 Lead Compounds from the Natural World PLANT EXTRACTS OPIUM - MorphineOPIUM - Morphine CINCHONA BARK - QuinineCINCHONA BARK - Quinine YEW TREE - TaxolYEW TREE - Taxol

1 © 4.3 Lead Compounds from the Natural World PLANT EXTRACTS WILLOW TREE - SALICYLIC ACID COCA BUSH - COCAINE Aspirin Procaine

1 © 4.3 Lead Compounds from the Natural World VENOMS AND TOXINS Captopril(anti-hypertensive) Teprotide

1 © 4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS Agonist Agonist

1 © 4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS Antagonist Antagonist

1 © PRONTOSIL 4.4 Lead Compounds from the Synthetic World

1 © SULFANILAMIDE

1 © TNT 4.4 Lead Compounds from the Synthetic World

1 © RUBBER INDUSTRY ANTABUSE 4.4 Lead Compounds from the Synthetic World

1 © AUTOMATED SYNTHETIC MACHINES COMBINATORIAL SYNTHESIS

1 © RESIN BEAD AMINO ACID AMINO ACIDS X PEPTIDE 4.4 Lead Compounds from the Synthetic World COMBINATORIAL SYNTHESIS - PEPTIDE SYNTHESIS

1 © N N YO CHR 1 R 2 RESIN BEAD 4.4 Lead Compounds from the Synthetic World COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS

1 © RESIN BEADN N O R2R2 R3R3 H 4.4 Lead Compounds from the Synthetic World COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS

1 © N N O O EtO O R2R2 R3R3 R4R4 R5R5 RESIN BEAD 4.4 Lead Compounds from the Synthetic World COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS

1 © N N N NHNNHN O R2R2 R3R3 R4R4 R5R5 RESIN BEAD 4.4 Lead Compounds from the Synthetic World COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS

1 © N N YN O R2R2 R3R3 R4R4 R5R5 HNHNHNHN RESIN BEAD 4.4 Lead Compounds from the Synthetic World COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS

1 © The Past Lead Compound TargetsTargets Lead compounds The Future 4.5 Lead Compounds - Impact of the human genome project

1 © 4.6 Lead Compounds - de novo design

1 © X-RAY CRYSTALLOGRAPHY

1 © 4.6 Lead Compounds - de novo design PROTEIN STRUCTURE

1 © Receptor 4.6 Lead Compounds - de novo design

1 © Scaffold CO 2 - HO IONICBOND H- BON D VDWBOND Scaffold H3NH3N + O CH 3

1 © N HN O S O ONHN N N H2NH2NH2NH2N S O OON THYMIDYLATE KINASE INHIBITOR ANTICANCER AGENT LEAD COMPOUND Optimisation 4.6 Lead Compounds - de novo design

1 © 4.7 Design of Lead Compounds using NMR Spectroscopy NMR SPECTROSCOPY

1 © Binding Site Protein 4.7 Design of Lead Compounds using NMR Spectroscopy

1 © Protein NO OBSERVABLE BIOLOGICAL EFFECT 4.7 Design of Lead Compounds using NMR Spectroscopy

1 © 13 C NMR C C CH CH CH CH 2 CH Design of Lead Compounds using NMR Spectroscopy

1 © CH 2 CH Design of Lead Compounds using NMR Spectroscopy 13 C NMR C C CH CH CH CH 2 CH 3

1 © Protein 4.7 Design of Lead Compounds using NMR Spectroscopy Optimiseepitope

1 © Protein 4.7 Design of Lead Compounds using NMR Spectroscopy OptimiseepitopeOptimiseepitope

1 © Protein 4.7 Design of Lead Compounds using NMR Spectroscopy OptimiseepitopeOptimiseepitope Link

1 © LEAD COMPOUND 4.7 Design of Lead Compounds using NMR Spectroscopy

1 © Me Design of a lead compound as an immunosuppressant 4.7 Design of Lead Compounds using NMR Spectroscopy Epitope A Epitope B

1 © Me Design of a lead compound as an immunosuppressant 4.7 Design of Lead Compounds using NMR Spectroscopy Lead compound