Protein structure similarity clustering (PSSC) and natural product structure as inspiration sources for drug development and chemical genomics

被引:45
作者
Dekker, FJ
Koch, MA
Waldmann, H
机构
[1] Max Planck Inst Mol Physiol, Dept Biol Chem, D-44227 Dortmund, Germany
[2] Univ Dortmund, Fachbereich 3, D-44227 Dortmund, Germany
关键词
D O I
10.1016/j.cbpa.2005.03.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Finding small molecules that modulate protein function is of primary importance in drug development and in the emerging field of chemical genomics. To facilitate the identification of such molecules, we developed a novel strategy making use of structural conservatism found in protein domain architecture and natural product inspired compound library design. Domains and proteins identified as being structurally similar in their ligand-sensing cores are grouped in a protein structure similarity cluster (PSSC). Natural products can be considered as evolutionary pre-validated ligands for multiple proteins and therefore natural products that are known to interact with one of the PSSC member proteins are selected as guiding structures for compound library synthesis. Application of this novel strategy for compound library design provided enhanced hit rates in small compound libraries for structurally similar proteins.
引用
收藏
页码:232 / 239
页数:8
相关论文
共 53 条
[31]   Dual-specificity phosphatases as targets for antineoplastic agents [J].
Lyon, MA ;
Ducruet, AP ;
Wipf, P ;
Lazo, JS .
NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (12) :961-976
[32]   A transgenic model of visceral obesity and the metabolic syndrome [J].
Masuzaki, H ;
Paterson, J ;
Shinyama, H ;
Morton, NM ;
Mullins, JJ ;
Seckl, JR ;
Flier, JS .
SCIENCE, 2001, 294 (5549) :2166-2170
[33]   Medicinal chemistry of target family-directed masterkeys [J].
Müller, G .
DRUG DISCOVERY TODAY, 2003, 8 (15) :681-691
[34]   Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess [J].
New, MI ;
Wilson, RC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (22) :12790-12797
[35]   Natural products as sources of new drugs over the period 1981-2002 [J].
Newman, DJ ;
Cragg, GM ;
Snader, KM .
JOURNAL OF NATURAL PRODUCTS, 2003, 66 (07) :1022-1037
[36]  
ORNING L, 1991, J BIOL CHEM, V266, P1375
[37]   Evolution of domain families [J].
Ponting, CP ;
Schultz, J ;
Copley, RR ;
Andrade, MA ;
Bork, P .
ADVANCES IN PROTEIN CHEMISTRY, VOL 54: ANALYSIS OF AMINO ACID SEQUENCES, 2000, 54 :185-244
[38]   Acetylcholinesterase inhibitors: novel activities of old molecules [J].
Racchi, M ;
Mazzucchelli, M ;
Porrello, E ;
Lanni, C ;
Govoni, S .
PHARMACOLOGICAL RESEARCH, 2004, 50 (04) :441-451
[39]   Biological mechanism profiling using an annotated compound library [J].
Root, DE ;
Flaherty, SP ;
Kelley, BP ;
Stockwell, BR .
CHEMISTRY & BIOLOGY, 2003, 10 (09) :881-892
[40]  
Rose S, 2002, DRUG DISCOV TODAY, V7, P133