drug targets b fredholm

8/6/2019 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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drug targets b fredholm

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