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

被引：12

作者：

Baker, Lisa M. ^{[1
]}

Aimon, Anthony ^{[2
,3
]}

Murray, James B. ^{[1
]}

Surgenor, Allan E. ^{[1
]}

Matassova, Natalia ^{[1
]}

Roughley, Stephen D. ^{[1
]}

Collins, Patrick M. ^{[2
]}

Krojer, Tobias ^{[4
]}

von Delft, Frank ^{[2
,3
,4
,5
]}

Hubbard, Roderick E. ^{[1
,6
]}

机构：

[1] Vernalis R&D Ltd, Granta Pk, Cambridge CB21 6GB, England

[2] Diamond Light Source Ltd, Harwell Sci & Innovat Campus, Didcot OX11 0QX, Oxon, England

[3] Rutherford Appleton Lab, Res Complex Harwell RCaH, Didcot OX11 0FA, Oxon, England

[4] Univ Oxford, Struct Genom Consortium SGC, Oxford OX3 7DQ, England

[5] Univ Johannesburg, Dept Biochem, ZA-2006 Auckland Pk, South Africa

[6] Univ York, YSBL, York YO10 5DD, N Yorkshire, England

来源：

COMMUNICATIONS CHEMISTRY | 2020年 / 3卷 / 01期

基金：

巴西圣保罗研究基金会; 加拿大创新基金会;

关键词：

D O I：

10.1038/s42004-020-00367-0

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页数：11

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