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Allostery in Drug Discovery

Objective

Most current drugs are designed to bind directly to the primary active sites (also known as orthosteric sites) of their biological targets. Allosteric modulators offer a powerful yet underexploited therapeutic approach. They can elicit a richer variety of biological responses and, since they target less conserved binding sites, higher selectivity and less adverse effects may be obtained (Changeux, Drug Disc Today 2013). This proposal aims to train a new generation of scientists in exploiting the concept of allostery in drug design, putting together a whole array of technologies to identify and characterize allosteric modulators of protein function that will be applied to therapeutically relevant systems. Our approach is based on a combination of experimental and simulation techniques, including fragment Screening with structural characterization (X-ray, NMR, H/D exchange), proteomics (MS/MS), ITC, DNA encoding libraries, Virtual Screening, Molecular Dynamics simulations-based methods, Synthetic Chemistry, and in vitro and cellular assays for the verification of results. It should also be noted that allosteric targeting need not be achieved solely through the design of synthetic small molecules but also can also be reached via conformationally specific allosteric antibodies, which represents an important field of future research. There are already clear examples of monoclonal antibodies that allosterically target ion channels (Lee et al., 2014b), GPCRs (Mukund et al., 2013), and RTKs (De Smet et al., 2014), as well as cytokine and integrin receptors (Rizk et al., 2015; Schwarz et al., 2006).

Call for proposal

H2020-MSCA-ITN-2020
See other projects for this call

Coordinator

IDRYMA IATROVIOLOGIKON EREUNON AKADEMIAS ATHINON
Address
Soranou Efesiou 4
115 27 Athina
Greece
Activity type
Research Organisations
EU contribution
€ 243 017,64

Participants (12)

UNIVERSITAT WIEN
Austria
EU contribution
€ 264 207,24
Address
Universitatsring 1
1010 Wien
Activity type
Higher or Secondary Education Establishments
UNIVERSITAT DE BARCELONA
Spain
EU contribution
€ 501 809,76
Address
Gran Via De Les Corts Catalanes 585
08007 Barcelona
Activity type
Higher or Secondary Education Establishments
FORSCHUNGSZENTRUM JULICH GMBH
Germany
EU contribution
€ 252 788,40
Address
Wilhelm Johnen Strasse
52428 Julich
Activity type
Research Organisations
CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany
EU contribution
€ 252 788,40
Address
Chariteplatz 1
10117 Berlin
Activity type
Higher or Secondary Education Establishments
TERMESZETTUDOMANYI KUTATOKOZPONT
Hungary
EU contribution
€ 229 715,28
Address
Magyar Tudosok Korutja 2
1117 Budapest
Activity type
Higher or Secondary Education Establishments
FORSCHUNGSVERBUND BERLIN EV
Germany
EU contribution
€ 252 788,40
Address
Rudower Chaussee 17
12489 Berlin
Activity type
Research Organisations
KAROLINSKA INSTITUTET
Sweden
EU contribution
€ 281 982,96
Address
Nobels Vag 5
17177 Stockholm
Activity type
Higher or Secondary Education Establishments
HEPTARES THERAPEUTICS LIMITED
United Kingdom
EU contribution
€ 303 172,56
Address
Granta Park Great Abington
CB21 6DG Cambridge
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
UNIVERSITE DE STRASBOURG
France
EU contribution
€ 274 802,04
Address
Rue Blaise Pascal 4
67081 Strasbourg
Activity type
Higher or Secondary Education Establishments
MERCK HEALTHCARE KGAA
Germany
EU contribution
€ 252 788,40
Address
Frankfurter Strasse 250
64293 Darmstadt
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
JANSSEN PHARMACEUTICA NV
Belgium
EU contribution
€ 256 320
Address
Turnhoutseweg 30
2340 Beerse
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
THE UNIVERSITY OF BIRMINGHAM
United Kingdom
EU contribution
€ 303 172,56
Address
Edgbaston
B15 2TT Birmingham
Activity type
Higher or Secondary Education Establishments