Project description
Towards the efficient design of protein-targeting drugs
Proteolysis-targeting chimeras (PROTACs) are emerging as promising therapeutic molecules due to their capacity to degrade protein targets. PROTACs consist of a protein-targeting moiety and one that binds an E3 ubiquitin ligase responsible for target protein degradation. Currently, PROTAC design is an empirical process. Scientists of the EU-funded SBPD In-Silico project aim to facilitate PROTAC design based on structure. To achieve this, they will investigate the molecular mechanism by which PROTACs attract protein targets and the E3 ligase to form a complex. This information will be used to expand the available PROTAC molecules, setting the ground for a powerful new therapeutic modality against undruggable targets.
Objective
Proteolysis Targeting Chimeras (PROTACs) are small molecules that induce the degradation of target proteins of interest and have shown considerable promise as novel therapeutic agents. PROTACs are heterobifunctional compounds containing one moiety that binds to the target protein of interest and one that binds to an E3 ubiquitin ligase. Recruitment of the E3 ligase leads to ubiquitination and subsequent degradation of the target by the proteasome. The design of PROTACs largely remains an empirical process because of an insufficient understanding of the molecular basis for productive recruitment of target and E3 ligase into a ternary complex. Furthermore, there are only a handful of small-molecule ligands for E3 ligases that are amenable for PROTAC conjugation, so expanding the chemical space to PROTAC design is an important direction for the field. Virtual screening and structure-based drug design are powerful approaches for designing of drug-like molecules but their application to PROTAC design is still in its infancy. The structural complexity of the ternary complex central to PROTAC activity, and the chemical complexity of PROTAC molecules, are amongst some of the main challenges to structure-based PROTAC design. The goal of this proposal is to develop novel methodologies to contribute to systematically address these important challenges. The long-term goal of this proposal is to develop structure-based PROTAC design as an efficient, universally applicable platform for prediction, designing, and screening of effective PROTAC degraders of target proteins. The success in this project will pave the way to efficiently degrading “undruggable” targets as a powerful new modality of chemical intervention into biology and disease.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine medicinal chemistry
- natural sciences biological sciences biochemistry biomolecules proteins
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2019
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
DD1 4HN Dundee
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.