Chapter 4. Considering the Molecular Conformational Flexibility in QSAR Studies

GARCIA, J.; DUCHOWICZ, P. R.; CASTRO, E. A.

Chemometrics Applications and Research. QSAR in Medicinal Chemistry

CRC Press-Taylor&Francis Group

Año: 2016; p. 129 - 158

Conformational flexibility is a crucial aspect to be considered from the molecular structure for obtaining predictive QSAR models. We develop two simple algorithms that are based in the Stepwise Inclusion procedure and the Replacement Method, which introduce conformational flexibility in two different ways: i. by an iterative method and ii. by taking into account the descriptor values of all the conformations at once. We apply such algorithms to predict the apparent second order inactivation rate constant for different serine protease inhibitors based on the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold, and also to structurally heterogeneous inhibitors of the Angiotensin Converting Enzyme. Present approach improves the results obtained by both the Stepwise Inclusion technique and the Replacement Method.