Principles of early drug discovery

被引:1750
作者
Hughes, J. P. [2 ]
Rees, S. [3 ]
Kalindjian, S. B. [1 ]
Philpott, K. L. [1 ]
机构
[1] Kings Coll London, London SE1 1UL, England
[2] Medimmune Inc, Cambridge, England
[3] GlaxoSmithKline, Stevenage, Herts, England
基金
英国惠康基金; 英国医学研究理事会;
关键词
drug discovery; high throughput screening; target identification; target validation; hit series; assay development; screening cascade; lead optimization; SCN9A;
D O I
10.1111/j.1476-5381.2010.01127.x
中图分类号
R9 [药学];
学科分类号
100702 [药剂学];
摘要
Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12-15 years and cost in excess of $1 billion. The idea for a target can come from a variety of sources including academic and clinical research and from the commercial sector. It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development.
引用
收藏
页码:1239 / 1249
页数:11
相关论文
共 25 条
[1]
Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo [J].
Abell, AN ;
Rivera-Perez, JA ;
Cuevas, BD ;
Uhlik, MT ;
Sather, S ;
Johnson, NL ;
Minton, SK ;
Lauder, JM ;
Winter-Vann, AM ;
Nakamura, K ;
Magnuson, T ;
Vaillancourt, RR ;
Heasley, LE ;
Johnson, GL .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (20) :8948-8959
[2]
Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses [J].
Bertram, Lars ;
Tanzi, Rudolph E. .
NATURE REVIEWS NEUROSCIENCE, 2008, 9 (10) :768-778
[3]
Knowledge based identification of MAO-B selective inhibitors using pharmacophore and structure based virtual screening models [J].
Boppana, Kiran ;
Dubey, P. K. ;
Jagarlapudi, Sarma A. R. P. ;
Vadivelan, S. ;
Rambabu, G. .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2009, 44 (09) :3584-3590
[4]
The promises and pitfalls of RNA-interference-based therapeutics [J].
Castanotto, Daniela ;
Rossi, John J. .
NATURE, 2009, 457 (7228) :426-433
[5]
Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain [J].
Chessell, IP ;
Hatcher, JP ;
Bountra, C ;
Michel, AD ;
Hughes, JP ;
Green, P ;
Egerton, J ;
Murfin, M ;
Richardson, J ;
Peck, WL ;
Grahames, CBA ;
Casula, MA ;
Yiangou, Y ;
Birch, R ;
Anand, P ;
Buell, GN .
PAIN, 2005, 114 (03) :386-396
[6]
An SCN9A channelopathy causes congenital inability to experience pain [J].
Cox, James J. ;
Reimann, Frank ;
Nicholas, Adeline K. ;
Thornton, Gemma ;
Roberts, Emma ;
Springell, Kelly ;
Karbani, Gulshan ;
Jafri, Hussain ;
Mannan, Jovaria ;
Raashid, Yasmin ;
Al-Gazali, Lihadh ;
Hamamy, Henan ;
Valente, Enza Maria ;
Gorman, Shaun ;
Williams, Richard ;
McHale, Duncan P. ;
Wood, John N. ;
Gribble, Fiona M. ;
Woods, C. Geoffrey .
NATURE, 2006, 444 (7121) :894-898
[7]
Dunne A, 2009, METHODS MOL BIOL, V565, P239, DOI 10.1007/978-1-60327-258-2_12
[8]
High-throughput screening: Update on practices and success [J].
Fox, Sandra ;
Farr-Jones, Shauna ;
Sopchak, Lynne ;
Boggs, Amy ;
Nicely, Helen Wang ;
Khoury, Richard ;
Biros, Michael .
JOURNAL OF BIOMOLECULAR SCREENING, 2006, 11 (07) :864-869
[9]
HTS and hit finding in academia - from chemical genomics to drug discovery [J].
Frearson, Julie A. ;
Collie, Iain T. .
DRUG DISCOVERY TODAY, 2009, 14 (23-24) :1150-1158
[10]
HENNING SW, 2002, CURR DRUG DISCOV MAY, P17