Chemists – biologists What can be done together? Supramolecular systems in chemistry and biology Tuapse, Septembre 27 – October 2, 2008 Marcel Hibert Laboratoire dInnovation Thérapeutique Drug Discovery Center Faculté de Pharmacie Strasbourg (France)

innocent question? Chemists – biologists : What can be done together?

innocent question? Nothing is OK Chemists – biologists : What can be done together?

innocent question? Nothing is OK More if affinity Chemists – biologists : What can be done together?

1- We are all big lots of atoms and molecules water : 60% ; bones: 3 kg; organic molecules : 25 kg about molecules bound via reversible interactions « All what exists in this world is made of atoms and vacuum » Democritis (420 bc) Human being = supramolecular assembly Supramolecular chemistry – medicinal chemistry

1- We are all big lots of atoms and molecules water : 60% ; bones: 3 kg; organic molecules : 25 kg about molecules bound via reversible interactions « All what exists in this world is made of atoms and vacuum » Democritis (420 bc) « Life is a molecular dynamic equilibrium » Jacques Monod ( 1950) 2- All biological functions are supramolecular function Human being = supramolecular assembly Supra-biomolecular complex Supramolecular chemistry – medicinal chemistry

1- We are all big lots of atoms and molecules water : 60% ; bones: 3 kg; organic molecules : 25 kg about molecules bound via reversible interactions « All what exists in this world is made of atoms and vacuum » Democritis (420 bc) « Life is a molecular dynamic equilibrium » Jacques Monod ( 1950) 2- All biological functions are supramolecular function Human being = supramolecular assembly Supra-biomolecular complex Supramolecular chemistry – medicinal chemistry Emil Fisher Paul Ehrlich

1- We are all big lots of atoms and molecules water : 60% ; bones: 3 kg; organic molecules : 25 kg about molecules bound via reversible interactions « All what exists in this world is made of atoms and vacuum » Democritis (420 bc) « Life is a molecular dynamic equilibrium » Jacques Monod ( 1950) 2- All biological functions are supramolecular function Human being = supramolecular assembly Supra-biomolecular complex Supramolecular chemistry – medicinal chemistry Emil Fisher Paul EhrlichJ-M Lehn

Four elementary biological functions Recognition function receptor ligand recognition Catalysis enzyme products substrate Chemical reaction recognition eg adrenaline receptor eg protease, hydrolase,etc. Supramolecular chemistry – medicinal chemistry

Four elementary biological functions Transport Architecture carrier substrate translocation recognition somewhere elsewhere recognition + eg ion channels, hormone transport eg cell membrane, DNA Supramolecular chemistry – medicinal chemistry

Disease Understanding life integrated function (tissue, cell) elementary function suprabiomolecular complex Supramolecular chemistry – medicinal chemistry receptor ligand G protein signal

Cell membrane in out G protein coupling site Hormone binding site Oxytocine and love

Disease Understanding life integrated function (tissue, cell) elementary function suprabiomolecular complex Supramolecular chemistry – medicinal chemistry receptor ligand G protein signal

Structural Approach Experimental or theoretical 3D structure Ligand design ligand Rational Screening Molecules natural substances de novo synthesis screening target proteins Cloning expression Ligands (hits) Chemical library Target library Targets Synthesis, biology rationalize and accelerate ligand discovery... rationalize accelerate Supramolecular chemistry – medicinal chemistry

Discovery of ligands : screening approach Challenge : discover ligands + compounds targets screening research tools DRUGS assays Supramolecular chemistry – medicinal chemistry

molecules natural substances 20 laboratories High diversity High drugability …towards a European Compound Library (FP7) molecules... Supramolecular chemistry – medicinal chemistry

Available : natural substances synthetic compounds from laboratories de novo : combinatorial chemistry targetted libraries « Laboratory Compound Library » collect register store in plates molecules... Supramolecular chemistry – medicinal chemistry

collect compounds central database structure / activity data Copies in 96 well microtiterplates standard storage Strasbourg molecules diverse and drug-like molecules Supramolecular chemistry – medicinal chemistry

State of the art - Sept (very under estimated) Scientific : 70 collaborative projects initiated between chemists and biologists 146 screning campaigns, 95 validated hits, 20 publications, 13 patents, 24 application to calls for projects, 6 european projects submitted, 3 funded industrial : molecule transfer partnership 26 projects in partnership with industry 1 compound in clinics (Ilkirch/Washington/Minozac) 9 start-up companies 5 Septembre 2005 Supramolecular chemistry – medicinal chemistry