Abstract
We present a new tool for hepatocarcinogenicity evaluation of drug candidates in rodents. ToxDBScan is a web tool offering quick and easy similarity screening of new drug candidates against two large-scale public databases, which contain expression profiles for substances with known carcinogenic profiles: TG-GATEs and DrugMatrix. ToxDBScan uses a set similarity score that computes the putative similarity based on similar expression of genes to identify chemicals with similar genotoxic and hepatocarcinogenic potential. We propose using a discretized representation of expression profiles, which use only information on up- or down-regulation of genes as relevant features. Therefore, only the deregulated genes are required as input. ToxDBScan provides an extensive report on similar compounds, which includes additional information on compounds, differential genes and pathway enrichments. We evaluated ToxDBScan with expression data from 15 chemicals with known hepatocarcinogenic potential and observed a sensitivity of 88%. Based on the identified chemicals, we achieved perfect classification of the independent test set. ToxDBScan is publicly available from the ZBIT Bioinformatics Toolbox.
Highlights
Developing new drugs is a very cost-intensive process
We present a new tool for the hepatocarcinogenicity evaluation of drug candidates in rodents
We developed a new similarity scoring method for gene expression profiles that allows robust identification of chemicals with similar hepatocarcinogenic and genotoxic potential
Summary
Developing new drugs is a very cost-intensive process. Estimates of the overall cost for developingFood and Drug Administration (FDA) approved drugs range from $160 million to $1.8 billion for one drug, based on success rates of only 12% to 23% for drugs entering the clinical phase [1]. Developing new drugs is a very cost-intensive process. Estimates of the overall cost for developing. Food and Drug Administration (FDA) approved drugs range from $160 million to $1.8 billion for one drug, based on success rates of only 12% to 23% for drugs entering the clinical phase [1]. Low success rates in combination with high requirements for approval by the FDA or similar agencies lead to the immense costs per approved drug. Between 40 and 65 percent of the total cost is spent during the preclinical phase [1]. While clinical trials are generally more expensive than preclinical trials, the success rate is much lower for preclinical trials. A larger number of preclinical trials is required per approved drug, which leads to high costs accumulating in the preclinical phase
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