Considering the molecular conformational flexibility in QSAR studies

JAVIER GARCIA; PABLO R. DUCHOWICZ; EDUARDO A. CASTRO

Chemometrics Applications and Research QSAR in Medicinal Chemistry

CRC Press

Año: 2015; p. 1 - 8

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.