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Development and validation of a robust QSAR model for prediction of carcinogenicity of drugs

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Title Development and validation of a robust QSAR model for prediction of carcinogenicity of drugs
 
Creator Kar, Supratik
Roy, Kunal
 
Subject QSAR
Carcinogenicity
Drugs
Chemometric tools
Validation
 
Description 111-122
Carcinogenicity is one of the toxicological
endpoints causing the highest concern. Also, the standard bioassays in rodents
used to assess the carcinogenic potential of chemicals and drugs are extremely
long, costly and require the sacrifice of large numbers of animals. For these reasons, we have attempted development of a global quantitative
structure–activity relationship (QSAR) model using a data set of 1464 compounds
(the Galvez data set available from http://www.uv.es/~galvez/tablevi.pdf),
including many marketed drugs for
their carcinogenesis potential. Though experimental
toxicity testing using animal models is unavoidable for new drug candidates at
an advanced stage of drug development, yet the developed global QSAR model can in silico predict the
carcinogenicity of new drug compounds to provide a tool for initial screening
of new drug candidate molecules with reduced number of animal testing, money
and time. Considering large number of data points with diverse structural
features used for model development (ntraining = 732) and model
validation (ntest = 732), the model developed in this study has an
encouraging statistical quality (leave-one-out Q2 = 0.731, R2pred
= 0.716). Our developed model suggests that higher lipophilicity values and conjugated ring systems, thioketo and nitro groups
contribute positively towards drug carcinogenicity. On the contrary, tertiary and secondary nitrogens, phenolic, enolic and
carboxylic OH fragments and presence of three-membered rings reduce the
carcinogenicity. Branching, size and shape are found to be crucial factors for
drug-induced carcinogenicity. One may consider all these points to reduce
carcinogenic potential of the molecules.
 
Date 2011-04-26T07:02:14Z
2011-04-26T07:02:14Z
2011-04
 
Type Article
 
Identifier 0975-0959 (Online); 0301-1208 (Print)
http://hdl.handle.net/123456789/11614
 
Language en_US
 
Rights CC Attribution-Noncommercial-No Derivative Works 2.5 India
 
Publisher NISCAIR-CSIR, India
 
Source IJBB Vol.48(2) [April 2011]