Dear all,
I was wondering whether there is already anything done on the scoring of the different fragment hits? How they compare to each other in terms of affinity? Any wetlab data that is already available perhaps?
This would make it significantly easier for medicinal chemists to design new (hopefully better) inhibitors.
Kind regards.
Hi, sorry this post got buried. There will be affinity data after the next round of synthesis; however, we are just working off the fragment hits (many weak binders) right now.
There is an effort to do some docking and FEP of the proposed structures by @JohnChodera, @RGlen , and others here: Simulation planning
Thank you. I have done some covalent docking myself in an attempt to score the different covalent fragments. However, the overlay with the crystal structures were quite poor in most cases, probably due to the fact that these are very weak binders, making it difficult to predict the pose. But covalent docking could come in handy once we have some better binding molecules.
Quick reply from the XChem side; this is the challenge of fragment hit progression. Computational methods are performing well when the compounds are in a later stage (more potent). But there is no systematic approach to efficiently progress an ensemble of valuable starting points (that can be observed by x-ray) to a more complex structure that will capture interactions from the ensemble. So yes, just docking at this stage will not give you any strong answer and we are routinely struggling to get measurable potency of these fragments using biochemical/physical methods. Any suggestions are welcome 