Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures.

ABSTRACT: Fragment based methods are now widely used to identify starting points in drug discovery and generation of tools for chemical biology. A significant challenge is optimization of these weak binding fragments to hit and lead compounds. We have developed an approach where individual reaction mixtures of analogues of hits can be evaluated without purification of the product. Here, we describe experiments to optimise the processes and then assess such mixtures in the high throughput crystal structure determination facility, XChem. Diffraction data for crystals of the proteins Hsp90 and PDHK2 soaked individually with 83 crude reaction mixtures are analysed manually or with the automated XChem procedures. The results of structural analysis are compared with binding measurements from other biophys

SUBMITTER: Baker LM 

PROVIDER: S-EPMC9814918 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature