Medicine for Malaria Venture (MMV) had found a ligand through a high throughput screen. They developed a compound and improved its activity, and then asked Cresset Discovery to work backwards from the compound to determine the probable site of action at the protein target. The antimalarial target has been published in this paper: Nature 522 pg 315-320 2015.
MMV already had some resistance mutagenesis data. They observed residue changes in the protein that caused it to resist the medication and were able to assign a few residues that were important for the recognition. This gave us some clues to work on.
Cresset Discovery took this starting data and used it to build a homology protein model of the malarial parasitic protein. We then looked at the structure-activity relationships around the molecules of interest, carried out conformation sampling of the molecule and looked at the residues and the pocket that was the likely place of interaction of the molecule. Using this we developed a binding hypothesis for the molecule.
There were nine different possibilities for the conformation of the molecule. We slightly adjusted each of the conformations, looked at some different permutations of how the residues were placed and how they were orientated in the pocket. Then we took each of the ligand-protein interaction hypotheses, minimized them and looked at the ligand-protein’s binding energies. Based on these, we could judge which of the hypotheses were reasonable.
On the basis of one of these hypotheses we carried out a virtual screening exercise and a fragment replacement exercise. The ultimate aim of the project was to provide MMV with another chemotype for them to work on so that they have a back-up series for their published series, preserving the novel mode of action they had discovered. MMV’s next step will be to buy the compounds or have them synthesised and get them tested. The work from Cresset Discovery gave them some good ideas and certainly gave them the best chance of finding something from commercial compounds that they can buy.
