Abstract

Summary: The quality and predictivity of QSAR models used in drug design and development often depend on the tautomeric and valence structures used to represent the molecules of interest. This is because the location of hydrogen bonding groups, bond orders, and formal charges affect the values of atomic and molecular descriptors upon which the models are based. For descriptors such as partial charges, this dependence is typically due to basing atom typing on hybridization. The sp3- hybridized hydroxyl group in an enol, for example, is treated differently than its sp2-hybridized counterpart in a carbonyl, even though oxygen appears in both forms in some tautomers of a molecule. In the aqueous environment of interest in drug design applications, representing a compound as any one of its tautomers is likely to distort the QSAR model obtained. Even worse is the danger that choosing a tautomer present at low abundance will bias the model building process or the reliability of predictions or both. To address this problem, we are developing a descriptor generation method which is independent of tautomer and valence structure representation and will illustrate its application to the atomic descriptors used in S+pKa, which is our global model of protic ionization constants. Preliminary results will be shown and compared with the “traditional” approach along with a discussion of advantages and potential pitfalls of the method.

11th Annual German Conference on Chemoinformatics (GCC), November 8-10, 2015, Fulda, Germany

By Robert Fraczkiewicz, Marvin Waldman, Robert D. Clark