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H2020Doctoral network2021–2025

ALLODD · Allostery in Drug Discovery

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2021-09-01 → 2025-08-31
EU contribution
€3,627,681
Participants
14
Scheme
MSCA-ITN

Lines connect the coordinator with its partners.

Results in brief

Allostery in Drug Discovery

Most current drugs are designed to bind directly to the primary active sites (also known as orthosteric sites) of their biological targets. Drug discovery mainly focuses on the modulation or inhibition of protein function through small molecules that bind to their primary active sites. However, protein function may also be regulated through drug binding to distant sites, known as allosteric sites. 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 fewer adverse effects may be obtained. Over the course of four years, ALLODD brought together 13 Beneficiaries and 11 Partner Organizations from Academia and Industry from 12 countries across Europe. The project developed new computational and experimental platforms to detect allosteric ligands and sites, optimize allosteric ligands, create open datasets and tools, and contribute to scientific knowledge through dissemination, communication, and outreach activities. It supported the training and career development of 14 ESRs on Allostery in Drug Discovery through secondments, training events and activities, mentoring, and interdisciplinary collaboration. Overall, ALLODD has strengthened the scientific foundation and practical tools needed to make allosteric drug discovery a feasible approach in both academia and industry.

Data: CORDIS, © European Union

Project 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).

Original text from CORDIS.

Participants

  • IDRYMA IATROVIOLOGIKON EREUNON AKADEMIAS ATHINON · AthinaCoordinatorGreece
  • CHARITE - UNIVERSITAETSMEDIZIN BERLIN · BerlinGermany
  • FORSCHUNGSVERBUND BERLIN EV · BerlinGermany
  • FORSCHUNGSZENTRUM JULICH GMBH · JULICHGermany
  • HUN-REN TERMESZETTUDOMANYI KUTATOKOZPONT · BudapestHungary
  • JANSSEN PHARMACEUTICA NV · BeerseBelgium
  • KAROLINSKA INSTITUTET · STOCKHOLMSweden
  • MERCK HEALTHCARE KGAA · DarmstadtGermany
  • NXERA PHARMA UK LIMITED · CambridgeUnited Kingdom
  • THE UNIVERSITY OF BIRMINGHAM · BirminghamUnited Kingdom
  • UNIVERSITAT DE BARCELONA · BarcelonaSpain
  • UNIVERSITAT WIEN · WienAustria
  • UNIVERSITE DE STRASBOURG · StrasbourgFrance
  • Universita' degli Studi di Urbino Carlo Bo · UrbinoItaly

Links

Data: CORDIS, © European Union