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American Journal of Drug Discovery and Development

Year: 2012 | Volume: 2 | Issue: 4 | Page No.: 184-193
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Authors

Qing Zhang

Ada Solidar

Nicholas J. Murgolo

Wynand Alkema

Wei Ding

Peter M. Groenen

Jonathan R. Greene

Eric L. Gustafson

Jan Klomp

Ellie D. Norris

Ping Qiu

Gerald J. Wyckoff

Gerald J. Wyckoff

Keywords

We examined the synonymous vs. nonsynonymous substitution rate ratios (Ka/Ks, aka evolutionary rate) between human and chimpanzee for 166 successful drug target genes and compared them with a larger (10,298) set of genes representative of average human-chimpanzee evolutionary rates. We found that evolutionary rates differ significantly between successfully marketed drug targets and the broader set of genes (p<0.005 by ANOVA). Evolutionary rates were lower for successfully marketed drug targets versus non-target genes (0.311 versus 0.497). This rate discrepancy demonstrates that more conserved genes, even within protein families such as GPCRs (successful target GPCRs 0.391 versus non-target GPCRs 0.855) and protein kinases (0.131 versus 0.337), are better targets for traditional small molecule drug development than less strongly constrained genes. Evolutionary rate, therefore, is a factor that could be taken into account when selecting candidate target genes for drug discovery, in addition to the biochemical properties of the proteins these genes encode. We suggest therefore, that links be established between identified disease-causal or -associated genes and genes that are suitable targets for traditional small molecule pharmaceutical development.
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How to cite this article

Qing Zhang, Ada Solidar, Nicholas J. Murgolo, Wynand Alkema, Wei Ding, Peter M. Groenen, Jonathan R. Greene, Eric L. Gustafson, Jan Klomp, Ellie D. Norris, Ping Qiu and Gerald J. Wyckoff, 2012. Selective Constraint: A Hallmark of Genes Successfully Targeted for Pharmaceutical Development. American Journal of Drug Discovery and Development, 2: 184-193.

DOI: 10.3923/ajdd.2012.184.193

URL: https://scialert.net/abstract/?doi=ajdd.2012.184.193

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