Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiLX )

Journal of Medicinal Chemistry
Matthew R BentleyMartin J Scanlon

Abstract

A bottleneck in fragment-based lead development is the lack of systematic approaches to elaborate the initial fragment hits, which usually bind with low affinity to their target. Herein, we describe an analysis using X-ray crystallography of a diverse library of compounds prepared using microscale parallel synthesis. This approach yielded an 8-fold increase in affinity and detailed structural information for the resulting complex, providing an efficient and broadly applicable approach to early fragment development.

References

Sep 23, 1997·Protein Science : a Publication of the Protein Society·L W GuddatJ L Martin
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Oct 24, 2001·The Journal of Organic Chemistry·Hugo E. GottliebAbraham Nudelman
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Nov 24, 2004·Journal of Chemical Information and Computer Sciences·Ian J BrunoA Guy Orpen
Apr 5, 2005·Acta Crystallographica. Section D, Biological Crystallography·Santosh PanjikarPaul A Tucker
May 26, 2005·Protein Expression and Purification·F William Studier
Feb 10, 2009·Nature Reviews. Microbiology·Begoña HerasJennifer L Martin
Apr 28, 2009·Journal of Synchrotron Radiation·P KraftB Schmitt
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Sep 23, 2009·Acta Crystallographica. Section D, Biological Crystallography·Santosh PanjikarPaul A Tucker
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·T Geoff G BattyeAndrew G W Leslie
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans
Apr 21, 2011·Journal of Medicinal Chemistry·Stephen D Roughley, Allan M Jordan
Mar 1, 2012·Journal of Chemical Information and Modeling·Simon J CottrellJohn W Liebeschuetz
May 26, 2012·Science·P Andrew Karplus, Kay Diederichs
Jun 5, 2013·Journal of Medicinal Chemistry·Steven R LaPlantePierre L Beaulieu
Jun 26, 2013·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans, Garib N Murshudov
Feb 1, 2014·Nature Reviews. Drug Discovery·Andrew L HopkinsCharles H Reynolds
Feb 21, 2014·British Journal of Clinical Pharmacology·Begoña HerasJennifer L Martin
Jul 16, 2016·Nature Reviews. Drug Discovery·Daniel A ErlansonHarren Jhoti
Oct 8, 2019·Acta Crystallographica. Section D, Structural Biology·Dorothee LiebschnerPaul D Adams

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Citations

Nov 11, 2020·Current Opinion in Structural Biology·Tobias KrojerFrank von Delft
Sep 3, 2021·Acta Crystallographica. Section D, Structural Biology·Alexander MetzManfred S Weiss
Dec 21, 2021·Journal of Medicinal Chemistry·Iwan J P de EschLouise Walsh

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