ISOTRAPSS · Isoform specific inhibition by transient protein state stabilization
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-09-15 → 2017-09-14
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Isoform specific inhibition by transient protein state stabilization
The project focussed on the development of a novel approach to small molecules drug design. A major problem for pharmaceutical R&D is that many small molecules fail to bind selectively to a disease-involved protein. Frequently a protein implicated in disease looks very similar to other proteins that should not be targeted by a small molecule. It is important for society to research new approaches to small molecule drug design that can contribute small molecules with greater binding selectivity, as this is associated with fewer side effects and greater likelihood that the small molecules may become viable drugs to treat diseases. The overall objectives of the project were to validate a drug design strategy that uses information about the dynamics of proteins (’molecular movies’). This differs from traditional strategies that leverage information about the structure of a protein (‘molecular pictures’). The approach pursued in ISOTRAPSS used the Cyclophilin family of proteins as a model system and had three main objectives. The first objective was to generate models of protein dynamics for selected Cyclophilin proteins starting from experimental data, and a novel methodology (aMD/MSM) that was developed for that purpose. The second objective was to validate a computational model that can rationalise structure-activity relationships for literature Cyclophilin ligands. This was pursued using software and methodologies developed for that purpose. The third objective was to combine the findings from the first two objectives to discover new Cyclophilin ligands. The work involved a combination of computational modelling, biophysical experiments, and organic syntheses.
Data: CORDIS, © European Union
Project objective
The rapid identification of synthetic molecules that selectively inhibit some proteins among families of closely related proteins is one of the major unsolved problems of modern drug discovery. If such ability was at hand, it would radically revise our definition of the ‘druggable’ genome. The goal of this proposal is to expand the state-of-the art of rational drug design with a new strategy that combines cutting edge computational techniques with modern experimental biophysical methods. We aim to achieve selective inhibition of proteins that are highly similar to other related proteins. To do so we will exploit concepts from energy landscape theory to identify transient conformational states of proteins that can be trapped by ligands to achieve extremely high binding selectivity. To provide proof of concept for such strategy, we will focus efforts on the therapeutically relevant cyclophilin protein family. Computational work will focus on: 1) unravelling the conformational preferences of the most common cyclophilin family members, and 2) clarification of current controversies regarding the binding mode and structure activity relationships of known selective ligands. Experimental work will involve the characterization of purchased or custom-synthesized ligands in in vitro assays and crystal structure analyses. Overall, this project proposes fundamental advances in rational drug design, therefore expanding opportunities for the development of future small molecule therapeutics.
Original text from CORDIS.
Participants
- THE UNIVERSITY OF EDINBURGH · EdinburghCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union