In-silico screening of high production volume chemicals for mutagenicity using the MCASE QSAR expert system.
Computational screening is suggested as a way to set priorities for further testing of high production volume (HPV) chemicals for mutagenicity and other toxic endpoints. Results are presented for batch screening of 2484 HPV chemicals to predict their mutagenicity in Salmonella typhimurium (Ames test). The chemicals were tested against 15 databases for Salmonella strains TA100, TA1535, TA1537, TA97 and TA98, both with metabolic activation (using rat liver and hamster liver S9 mix test) and without metabolic activation. Of the 2484 chemicals, 1868 are predicted to be completely nonmutagenic in all of the 15 data modules and 39 chemicals were found to contain structural fragments outside the knowledge of the expert system and therefore suggested for further evaluation. The remaining 616 chemicals were found to contain different biophores (structural alerts) believed to be linked to mutagenicity. The chemicals were ranked indescending order according to their predicted mutagenic potential and the first 100 chemicals with highest mutagenicity scores are presented. The screening result offers hope that rapid and inexpensive computational methods can aid in prioritizing the testing of HPV chemicals, save time and animals and help to avoid needless expense.
Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. gxk6@po.cwru.edu
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G
Klopman
S K
SK
Chakravarti
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Harris
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J
Ivanov
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RD
Saiakhov
D000818:Animals; D001711:Biotransformation; D006224:Cricetinae; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D005103:Expert Systems; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics