Accurate and interpretable computational modeling of chemical mutagenicity.
We describe a method for modeling chemical mutagenicity in terms of simple rules based on molecular features. A classification model was built using a rule-based ensemble method called RuleFit, developed by Friedman and Popescu. We show how performance compares favorably against literature methods. Performance was measured through the use of cross-validation and testing on external test sets. All data sets used are publicly available. The method automatically generated transparent rules in terms of molecular structure that agree well with known toxicology. While we have focused on chemical mutagenicity in demonstrating this method, we anticipate that it may be more generally useful in modeling other molecular properties such as other types of chemical toxicity.
Langham
James J
JJ
Cancer Research Institute, University of California, San Francisco, 2340 Sutter Street, San Francisco, California 94143-0128, USA. james.langham@jainlab.org
Jain
Ajay N
AN
D003198:Computer Simulation; D016208:Databases, Factual; D008956:Models, Chemical; D015394:Molecular Structure; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship
D009153:Mutagens
J Med Chem. 2005 Apr 7;48(7):2534-47
15801843
J Med Chem. 2005 Jan 13;48(1):312-20
15634026
Environ Health Perspect. 1991 Dec;96:11-5
1820251
Mol Divers. 2006 May;10(2):147-58
16721629
Nat Rev Drug Discov. 2007 Aug;6(8):636-49
17643090
J Chem Inf Model. 2006 May-Jun;46(3):991-8
16711717
Mutat Res. 2002 Jan 29;499(1):27-52
11804603
J Chem Inf Model. 2005 Jan-Feb;45(1):177-82
15667143
J Med Chem. 2006 May 18;49(10):2921-38
16686535
Bioorg Med Chem. 2004 May 1;12(9):2307-15
15080928
J Anat Physiol. 1868;2(2):224-42
17230757
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72
16381955
Bioinformatics. 2005 Oct 15;21(20):3940-1
16096348
Curr Opin Drug Discov Devel. 2006 May;9(3):314-25
16729727
Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6
18048412