ISOTRAPSS · Isoform specific inhibition by transient protein state stabilization

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.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз