We’ve also applied our approach to particularly challenging targets such as ubiquitin metabolism enzymes (deubiquitinases and E3 ligases) and epigenetic and epitranscriptomic targets.
Here you can find examples demonstrating how we successfully enabled FBDD campaigns on challenging targets.
Our client tasked us with setting up a complete “gene to lead” fragment-based drug discovery campaign.
Since the entire family is unprecedented, there were no “tool compounds” typically required to set up assays. As we progressed, further challenges presented themselves.
By capitalizing on our unique expertise in developing customized biophysical assays, we created a biologically relevant compound screening cascade in the absence of tool compounds. The cascade delivered chemically diverse sets of validated fragments that we successfully elaborated towards lead compounds using structural information that could only be gleaned through NMR.
Mettl3/Mettl14 is a large (90 kDa) heterodimeric “writer” complex that uses S-adenosyl methionine (SAM) as a cofactor. Identifying low affinity, validated fragment hits in the large amount of electron density derived from X-ray diffraction data was extremely difficult.
We developed a highly efficient structure pipeline capable of determining up to 10 sub 2Å structures per month which has been the basis for elaborating fragment hits to cellular activity and beyond. Multiple chemotypes are promising, allowing for a robust hit-to-lead campaign.