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ABSTRACT The need to decrease the time scale for clinical compound discovery has led to innovations at several stages in the process, including genomics/proteomics for target identification,

ultrahigh-throughput screening1 for lead identification, and structure-based drug design2 and combinatorial chemistry3 for lead optimization. A critical juncture in the process is the

identification of a proper lead compound, because a poor choice may generate costly difficulties at later stages. Lead compounds are commonly identified from high-throughput screens of large

compound libraries, derived from known substrates/inhibitors, or identified in computational prescreeusing X-ray crystal structures2,4,5,6. Structural information is often consulted to

efficiently optimize leads, but under the current paradigm, such data require preidentification and confirmation of compound binding. Here, we describe a new X-ray crystallography–driven

screening technique that combines the steps of lead identification, structural assessment, and optimization. The method is rapid, efficient, and high-throughput, and it results in detailed

crystallographic structure information. The utility of the method is demonstrated in the discovery and optimization of a new orally available class of urokinase inhibitors for the treatment

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customer support SIMILAR CONTENT BEING VIEWED BY OTHERS A ROBUST CRYSTAL STRUCTURE PREDICTION METHOD TO SUPPORT SMALL MOLECULE DRUG DEVELOPMENT WITH LARGE SCALE VALIDATION AND BLIND STUDY

Article Open access 05 March 2025 CHEMICAL SPACE DOCKING ENABLES LARGE-SCALE STRUCTURE-BASED VIRTUAL SCREENING TO DISCOVER ROCK1 KINASE INHIBITORS Article Open access 28 October 2022 A

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manual_. (Yale University Press, New Haven, CT; 1993). Google Scholar  Download references ACKNOWLEDGEMENTS We thank R. Meadows, S. Fesik, and S. Betz for helpful discussions and comments on

the manuscript; J. Wang for preparation of the urokinase protein; and S. Muchmore and T. Rockway for discussions on the technique. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department

of Structural Biology, Abbott Laboratories, Abbott Park, 60064-6098, IL Vicki L. Nienaber, Paul L. Richardson & Jonathan Greer * Department of Cancer Research, Abbott Laboratories,

Abbott Park, 60064-6098, IL Vered Klighofer, Jennifer J. Bouska & Vincent L. Giranda Authors * Vicki L. Nienaber View author publications You can also search for this author inPubMed 

Google Scholar * Paul L. Richardson View author publications You can also search for this author inPubMed Google Scholar * Vered Klighofer View author publications You can also search for

this author inPubMed Google Scholar * Jennifer J. Bouska View author publications You can also search for this author inPubMed Google Scholar * Vincent L. Giranda View author publications

You can also search for this author inPubMed Google Scholar * Jonathan Greer View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR

Correspondence to Vicki L. Nienaber. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Nienaber, V., Richardson, P., Klighofer, V. _et al._ Discovering

novel ligands for macromolecules using X-ray crystallographic screening. _Nat Biotechnol_ 18, 1105–1108 (2000). https://doi.org/10.1038/80319 Download citation * Received: 31 May 2000 *

Accepted: 27 July 2000 * Issue Date: October 2000 * DOI: https://doi.org/10.1038/80319 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get

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