Periodic Reporting for period 1 - ISOTRAPSS (Isoform specific inhibition by transient protein state stabilization)
Okres sprawozdawczy: 2015-09-15 do 2017-09-14
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.
In relation to the second work package, work published since the proposal submission indicated that a number of literature compounds were in fact artefacts. Attention focussed on another class of literature Cyclophilin ligands, but co-workers were unable to establish that these compounds do in fact, bind to Cyclophilins. Thus there was relatively little scope to pursue structure-activity relationship studies, and efforts focussed on the third work package. Instead the fellow has pursued collaborative work with co-workers to validate computational protocols for predictions of binding affinities. This has led to a number of publications.
In relation to the third work package, a combination of computational modelling with experiments carried out by co-workers has led to the discovery of a structurally novel class of Cyclophilin ligands that engage with Cyclophilins in a novel way. These compounds are under evaluation for possible patent filing, and a publication will report our findings in due course.
The project has also validated the use of alchemical free energy (AFE) methods for drug discovery. There is currently significant interest from industry in these methods. The protocols we tested and reported are currently being adopted by a number of pharmaceutical companies, thus the work done is already having an impact on industrial R&D processes.
The project has also generated novel classes of Cyclophilin ligands. While further developments are necessary before these compounds could become useful therapeutics, the strategy we used and the chemical structures obtained will influence ongoing and future Cyclophilin R&D programs worldwide one the work is published.