drug targets b fredholm
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Drivkrafter fr!lkemedelsutvecklingDrivkrafter fr!lkemedelsutveckling Ekonomiska realiteter
Medicinska behov
Vetenskapliga framsteg
New!knowledge!based!on
The!old!drug!discovery!paradigm
Physiological!experiments
(e.g.!New!hormone!or!transmitter
detected)
Unmet!medical!need
Target!identification
Lead!identification
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New!gene!found
The!new!drug!discovery!paradigmGeneproduct!expressed!inrelevant!tissue!in!man!or!animal
Geneproduct!expressed!incells!has!a!detectable!effectcompatible!with!a!role!in!disease
Target!identification
Expression!changed!indisease!or!mutation!in!genelinked!with!disease
Geneproduct!structurallysimilar!to!proteins!thathave!previously!beenreasonable!drug!targets
Unmet!medical!needLead!identification
Drug targets
Enzymes
Transporters
Ion!channels
Receptors!(about!50%)
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What!makes!receptors!special? Validation!strategies!available
High"throughput!screening!methods!
developed
Excellent!previous!experience! good!chemical!
libraries
e! o og ca !ro es!o !recep ors!ma e! em!especially!suitable!as!drug!targets
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The!biological roles of!receptors!make!themespecially suitable as!drug targets
Receptors!fulfill!regulatory!not!effector!roles
Receptors!have!evolved!to!possess!defined!
binding!pockets!which!affect!structure
Natural!ligands!provide!clues
Antagonists!perhaps!especially!useful!(and!
e n e y!eas er! o! eve op
The!signaling!machinery!starts!with!a!
receptor
Extracellular!signal
Receptor!molecule
Intracellular!signalproteins
Enzym
Transcription
faktor
Cytoskeletal!
protein
Metabolism Gene!expression Shape/movement
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Different!types!of!Receptors Nuclear!receptors
Kinase"coupled!receptors
Ligand!gated!ion!channels
G!protein!coupled!receptors
Nuclear!receptors
!
Structure
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Signal!transductionvia!kinase!coupledreceptors
Kinase!activity!of!the!receptor!induces!new!protein!interfaces!
for!intracellular!signaling
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Two!major!forms!of!signaling!switches
Protein!kinases!are!membrane!associated!or!soluble
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Ion!channels!are!needed!for!polar!molecules!to!
traverse!cell!membranes
AChR!subtypes.!The!
arrangements!of!subunits!
thought!to!exist!for!some!
prominent!AChR!subtypes!are!
indicated.!Acetylcholine"
binding!sites!are!depicted!at!
the!interface!between!the!+!
ACETYLCHOLINE!RECEPTOR! THE!
TYPICAL!LIGAND!OPERATED!!ION!CHNNEL
side!of!#!subunits!and!the!$!
side!of!%,!&,!',!(2!or!(4!
subunits.!Subunits!(1,!(3!and!
#5!are!depicted!as!occupying!
positions!that!do!not!participate!in!forming!
acetylcholine"binding!sites,!yet!
these!subunits!are!expected!to!
participate!in!and!influence!the!
concer e !con orma on!
changes!involved!in!activation!
and!desensitization!as!well!as!
to!contribute!to!the!properties!
of!the!cation!channel.!Modified!
from!Lindstrom!(2000b).
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G!protein!coupled!receptors
Many!subfamilies!of!!GPCR
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Overall structure of Ops*GaCT complex.
P Scheereret al. Nature455, 497-502 (2008) doi:10.1038/nature07330
Conceptual model for signal transmission from the active
receptor to the G protein by the Ga C terminus.
P Scheereret al. Nature455, 497-502 (2008) doi:10.1038/nature07330
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Binding!pocket!accessible!in!!2receptor,!but!not!in!rhodopsin!
Structure!of!adenosine!A2A receptorJaakola!et!al.!Science!Oct!2008.
!2A2A rhodopsin
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Comparison between rhodopsin,!!2 and!A2A
receptorsJaakola et!al.!Science!Oct 2008.
!2A2A rhodopsin
Roles!for!dimerization
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