Article

Selective Constraint: A Hallmark of Genes Successfully Targeted for Pharmaceutical Development

American Journal of Drug Discovery and Development 01/2012;

ABSTRACT 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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