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

DOI: 10.1038/s42004-020-00367-0 DOI Help

Authors: Lisa M. Baker (Vernalis (R&D) Ltd) , Anthony Aimon (Diamond Light Source; Research Complex at Harwell (RCaH)) , James B. Murray (Vernalis (R&D) Ltd) , Allan E. Surgenor (Vernalis (R&D) Ltd) , Natalia Matassova (Vernalis (R&D) Ltd) , Stephen D. Roughley (Vernalis (R&D) Ltd) , Patrick M. Collins (Diamond Light Source) , Tobias Krojer (tructural Genomics Consortium (SGC), University of Oxford) , Frank Von Delft (Diamond Light Source; Research Complex at Harwell (RCaH); Structural Genomics Consortium (SGC), University of Oxford; University of Johannesburg) , Roderick E. Hubbard (Vernalis (R&D) Ltd; YSBL, University of York)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Communications Chemistry , VOL 3

State: Published (Approved)
Published: September 2020

Open Access Open Access

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 biophysical techniques. This approach can transform early hit to lead optimisation and the lessons learnt from this study provide a protocol that can be used by the community.

Journal Keywords: Lead optimization; Screening

Subject Areas: Biology and Bio-materials, Medicine, Technique Development

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)