The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.
Fragment-Based Lead Discovery Using X-ray Crystallography
Abstract
Fragment screening offers an alternative to traditional screening for discovering new leads in drug discovery programs. This paper describes a fragment screening methodology based on high throughput X-ray crystallography. The method is illustrated against five proteins (p38 MAP kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments identified have weak potency (>100 microM) but are efficient binders relative to their size and may therefore represent suitable starting points for evolution to good quality lead compounds. The examples illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also that fragments can induce protein movement. We believe that the method has great potential for the discovery of novel lead compounds against a range of targets, and the companion paper illustrates how lead compounds have been identified for p38 MAP kinase starting from fragments such as those described in this paper.
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Cites
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139
Development and validation of a genetic algorithm for flexible docking 1 1Edited by F. E. Cohen
Jones, G., Willett, P., Glen, R. C., Leach, A. R., & Taylor, R. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0897 · Cited by 6,763
Cited by
Twenty years on: the impact of fragments on drug discovery
Erlanson, D. A., Fesik, S. W., Hubbard, R. E., Jahnke, W., & Jhoti, H. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.109 · Cited by 1,000
Self-citationCan we rationally design promiscuous drugs?
HOPKINS, A., MASON, J., & OVERINGTON, J. (2006) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2006.01.013 · Cited by 469
Adding calorimetric data to decision making in lead discovery: a hot tip
Ladbury, J. E., Klebe, G., & Freire, E. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3054 · Cited by 398
Protein X-ray Crystallography and Drug Discovery
Maveyraud, L., & Mourey, L. (2020) · Molecules · doi:10.3390/molecules25051030 · Cited by 269
State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors
Sheng, C., Dong, G., Miao, Z., Zhang, W., & Wang, W. (2015) · Chemical Society Reviews · doi:10.1039/c5cs00252d · Cited by 165
Metadata
- Authors
- Hartshorn, M. J., Murray, C. W., Cleasby, A., Frederickson, M., Tickle, I. J., & Jhoti, H.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2004-12-21
- Volume
- 48
- Issue
- 2
- Pages
- 403-413
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2134503191
- Cited by
- 422
- References
- 2
- FWCI
- 17.50
- Type
- journal article
- Language
- en
- Open access
- closed
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
