Quantitative systems-level determinants of drug targets
© Yao and Rzhetsky; licensee BioMed Central Ltd 2008
Published: 30 October 2008
Modern drug discovery tends to understand disease processes at the molecular level and then determine optimal molecular targets for drug intervention. Inferences have made from all available drug targets, such as how many drug targets there are, or how many novel drug targets could be potentially found in the human genome, to what functional families these proteins belong, and what structural properties make them bind to small molecules tightly and specifically. But all these are very intuitive and qualitative. The key question of which gene or protein in a disease process could be a successful drug target remains unanswered.
We also built a machine-learning model to demonstrate the usefulness of these quantitative descriptors for predicting drug targets. With increasing availability of experimental data, we foresee that screening the whole human genome for potential novel drug targets could be feasible in near future.
We found that genes associated with successful FDA-approved drugs have a number of properties at the network, sequence, and tissue-expression levels that significantly distinguish them from other human genes. Although the drug-target-selection guidelines that we suggest cannot replace expensive experiments, they can help pharmaceutical researchers narrow the prospective set of drug targets at the earliest stage of a drug development project. Specifically, when the pharmaceutical company must decide which target to pursue among pathologic pathways that are not fully understood, connectivity, betweenness, Cratio, and entropy might be useful quantitative estimates of each prospective target's expected success rate.
This article is published under license to BioMed Central Ltd.