MEASURING DIVERSITY - EXPERIMENTAL-DESIGN OF COMBINATORIAL LIBRARIES FOR DRUG DISCOVERY

被引：300
作者：
MARTIN, EJ
BLANEY, JM
SIANI, MA
SPELLMEYER, DC
WONG, AK
MOOS, WH
机构：
[1] Chiron Corp., Emeryville, California 94608-2916
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 1995年 / 38卷 / 09期
关键词：
D O I：
10.1021/jm00009a003
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Screening synthetic combinatorial libraries, such as mixtures of oligo(N-substituted)glycines, facilitates rapid drug lead discovery and optimization by vastly increasing the number of candidate molecules made and tested. Discovery efficiency and productivity can be further improved by using experimental design to maximize molecular diversity for a given library size or to bias the library with key features for a specific receptor. We describe new methods to quantify molecular diversity using descriptors that characterize lipophilicity, shape and branching, chemical functionality, and specific binding features. Experimental design methods select sets of side chains that are diverse in these properties, and ''flower plots'' allow the diversity to be graphically compared. We also quantify the overall diversity accessible to different families of combinatorial chemistry.
引用
收藏
页码：1431 / 1436
页数：6
相关论文
共 27 条
  • [1] Moos W.H., Green G.D., Pavia M.R., Recent Advances in the Generation of Molecular Diversity, Annu. Rep. Med. Chem., 28, (1993)
  • [2] Simon R.J., Kania R.S., Zuckermann R.N., Huebner V.D., Jewell D.A., Banville S., Ng S., Wang L., Rosenberg S., Marlowe C.K., Spellmeyer D.C., Tan R., Frankel A.D., Santi D.V., Cohen F.E., Bartlett P.A., Peptoids: A Modular Approach to Drug Discovery, Proc. Natl. Acad. Sci. U. S. A., 89, pp. 9367-9371, (1992)
  • [3] Zuckermann R.N., Martin E.J., Spellmeyer D.C., Stauber G.B., Shoemaker K.R., Kerr J.M., Figliozzi G.M., Siani M.A., Simon R.J., Banville S.C., Brown E.G., Wang L., Moos W.H., Discovery of Nanomolar Ligands for 7-Transmembrane G-Protein Coupled Receptors from a Diverse (N-Substituted)- Glycine Peptoid Library, J. Med. Chem., 37, pp. 2678-2685, (1994)
  • [4] Zuckermann R.N., Kerr J.M., Kent S.B.H., Moos W.H., Efficient method for the preparation of peptoids [oligo (N- substituted glycines)] by submonomer solid-phase synthesis, J. Am. Chem. Soc., 114, pp. 10646-10647, (1992)
  • [5] Siani M.A., Daylight directory ofpublically contributed programs, 4, (1994)
  • [6] MDL, Available Chemicals Directory, (1993)
  • [7] Brandon/SPECS, Brandon/SPECS Database and Compound Collection, (1993)
  • [8] Weininger D., Thor, (1993)
  • [9] James C.A., Weininger D., Scofield J., Daylight Toolkit Programmer’s Guide, (1994)
  • [10] Leo A., Calculating log Poet from Structures, Chem. Rev., 93, (1993)
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