Biospectra analysis: Model proteome characterizations for linking molecular structure and biological response

被引:64
作者
Fliri, AF [1 ]
Loging, WT [1 ]
Thadeio, PF [1 ]
Volkmann, RA [1 ]
机构
[1] Pfizer Global Res & Dev, Groton, CT 06340 USA
关键词
D O I
10.1021/jm050494g
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Establishing quantitative relationships between molecular structure and broad biological effects has been a long-standing goal in drug discovery. Evaluation of the capacity of molecules to modulate protein functions is a prerequisite for understanding the relationship between molecular structure and in vivo biological response. A particular challenge in these investigations is to derive quantitative measurements of a molecule's functional activity pattern across different proteins. Herein we describe an operationally simple probabilistic structure-activity relationship (SAR) approach, termed biospectra analysis, for identifying agonist and antagonist effect profiles of medicinal agents by using pattern similarity between biological activity spectra (biospectra) of molecules as the determinant. Accordingly, in vitro binding data (percent inhibition values of molecules determined at single high drug concentration in a battery of assays representing a cross section of the proteome) are useful for identifying functional effect profile similarity between medicinal agents. To illustrate this finding, the relationship between biospectra similarity of 24 molecules, identified by hierarchical clustering of a 1567 molecule dataset as being most closely aligned with the neurotransmitter dopamine, and their agonist or antagonist properties was probed. Distinguishing the results described in this study from those obtained with affinity-based methods, the observed association between biospectra and biological response profile similarity remains intact even upon removal of putative drug targets from the dataset (four dopaminergic [D-1/D-2/D-3/D-4] and two adrenergic [alpha(1), and alpha(2)] receptors). These findings indicate that biospectra analysis provides an unbiased new tool for forecasting structure-response relationships and for translating broad biological effect information into chemical structure design.
引用
收藏
页码:6918 / 6925
页数:8
相关论文
共 46 条
[1]  
AHN HS, 1978, LIFE SCI, V23, P507
[2]   BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF THE SEROTONIN (5-HT)1A-RECEPTOR LIGAND SPIROXATRINE [J].
BARRETT, JE ;
HOFFMANN, SM ;
OLMSTEAD, SN ;
FOUST, MJ ;
HARROD, C ;
WEISSMAN, BA .
PSYCHOPHARMACOLOGY, 1989, 97 (03) :319-325
[3]   Pharmacogenomic analysis: Correlating molecular substructure classes with microarray gene expression data [J].
Blower P.E. ;
Yang C. ;
Fligner M.A. ;
Verducci J.S. ;
Yu L. ;
Richman S. ;
Weinstein J.N. .
The Pharmacogenomics Journal, 2002, 2 (4) :259-271
[4]   Early administration of tiapride to young rats without long-lasting changes in the development of the dopaminergic system [J].
Bock, N ;
Moll, GH ;
Wicker, M ;
Pilz, J ;
Rüther, E ;
Banaschewski, T ;
Huether, G ;
Rothenberger, A .
PHARMACOPSYCHIATRY, 2004, 37 (04) :163-167
[5]  
BRAMANTI P, 1992, ARZNEIMITTEL-FORSCH, V42-2, P1403
[6]  
Clark B J, 1985, J Pharmacol, V16 Suppl 3, P101
[7]  
Corboz M. R., 2003, Autonomic & Autacoid Pharmacology, V23, P208, DOI 10.1111/j.1474-8673.2003.00298.x
[8]   Proteomic traces of speciation [J].
Deeds, EJ ;
Shakhnovich, B ;
Shakhnovich, EI .
JOURNAL OF MOLECULAR BIOLOGY, 2004, 336 (03) :695-706
[9]   (H-3) RAUWOLSCINE BEHAVES AS AN AGONIST FOR THE 5-HT1A RECEPTORS IN HUMAN FRONTAL-CORTEX MEMBRANES [J].
DEVOS, H ;
CZERWIEC, E ;
DEBACKER, JP ;
DEPOTTER, W ;
VAUQUELIN, G .
EUROPEAN JOURNAL OF PHARMACOLOGY-MOLECULAR PHARMACOLOGY SECTION, 1991, 207 (01) :1-8
[10]   Alpha2-adrenoceptor mediated co-release of dopamine and noradrenaline from noradrenergic neurons' in the cerebral cortex [J].
Devoto, P ;
Flore, G ;
Pira, L ;
Longu, G ;
Gessa, GL .
JOURNAL OF NEUROCHEMISTRY, 2004, 88 (04) :1003-1009