An alignment-free methodology for modelling field-based 3D-structure activity relationships using inductive logic programming

Autor: Ross D. King, Bård Buttingsrud, Bjørn K. Alsberg
Rok vydání: 2007
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Zdroj: Journal of Chemometrics. 21:509-519
ISSN: 1099-128X
0886-9383
DOI: 10.1002/cem.1056
Popis: Traditional 3D-quantitative structure–activity relationship (QSAR)/structure–activity relationship (SAR) methodologies are sensitive to the quality of an alignment step which is required to make molecular structures comparable. Even though many methods have been proposed to solve this problem, they often result in a loss of model interpretability. The requirement of alignment is a restriction imposed by traditional regression methods due to their failure to represent relations between data objects directly. Inductive logic programming (ILP) is a class of machine-learning methods able to describe relational data directly. We propose a new methodology which is aimed at using the richness in molecular interaction fields (MIFs) without being restricted by any alignment procedure. A set of MIFs is computed and further compressed by finding their minima corresponding to the sites of strongest interaction between a molecule and the applied test probe. ILP uses these minima to build easily interpretable rules about activity expressed as pharmacophore rules in the powerful language of first-order logic. We use a set of previously published inhibitors of factor Xa of the benzamidine family to discuss the problems, requirements and advantages of the new methodology. Copyright © 2007 John Wiley & Sons, Ltd.
Databáze: OpenAIRE
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