Towards new computational tools for predicting toxicity
Linnaeus University Dissertations
No 243/2016
T OWARDS NEW COMPUTATIONAL
TOOLS FOR PREDICTING TOXICITY
S WAPNIL C HAVAN
LINNAEUS UNIVERSITY PRESS
Towards new computational tools for predicting toxicity
Doctoral dissertation, Department of Chemistry and Biomedical Sciences,
Linnaeus University, Kalmar, Sweden, 2016
ISBN: 978-91-88357-04-5
Published by: Linnaeus University Press, 351 95 Växjö, Sweden
Printed by: Elanders Sverige AB, 2016
Abstract
Chavan, Swapnil (2016). Towards new computational tools for predicting toxicity,
Linnaeus University Dissertation No 243/2016, ISBN: 978-91-88357-04-5.
Written in English.
The toxicological screening of the numerous chemicals that we are exposed to
requires significant cost and the use of animals. Accordingly, more efficient
methods for the evaluation of toxicity are required to reduce cost and the number
of animals used. Computational strategies have the potential to reduce both the
cost and the use of animal testing in toxicity screening. The ultimate goal of this
thesis is to develop computational models for the prediction of toxicological
endpoints that can serve as an alternative to animal testing. In Paper I, an attempt
was made to construct a global quantitative structure-activity relationship (QSAR)
model for the acute toxicity endpoint (LD50 values) using the Munro database that
represents a broad chemical landscape. Such a model could be used for acute
toxicity screening of chemicals of diverse structures. Paper II focuses on the use of
acute toxicity data to support the prediction of chronic toxicity. The results of this
study suggest that for related chemicals having acute toxicities within a similar
range, their lowest observed effect levels (LOELs) can be used in read-across
strategies to fill gaps in chronic toxicity data. In Paper III a k-nearest neighbor (kNN) classification model was developed to predict human ether-a-go-go related
gene (hERG)-derived toxicity. The results suggest that the model has potential
for use in identifying compounds with hERG-liabilities, e.g. in drug development.
Keywords
Acute toxicity, chronic toxicity, hERG, k-NN, LD50, LOEL, Munro database,
QSAR, read-across, toxicity
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term ‘receptor’ is often used to refer to any target molecule with which a drug
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of a drug to a receptor is known as ‘<JM?affinity’;O@AD=A>9J=;=HLGJ=DA;ALK9
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