Application of 4D-QSAR studies to a series of raloxifene analogs and design of potential selective estrogen receptor modulators.
Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis was applied on a series of 54 2-arylbenzothiophene derivatives, synthesized by Grese and coworkers, based on raloxifene (an estrogen receptor-alpha antagonist), and evaluated as ERa ligands and as inhibitors of estrogen-stimulated proliferation of MCF-7 breast cancer cells. The conformations of each analogue, sampled from a molecular dynamics simulation, were placed in a grid cell lattice according to three trial alignments, considering two grid cell sizes (1.0 and 2.0 Å). The QSAR equations, generated by a combined scheme of genetic algorithms (GA) and partial least squares (PLS) regression, were evaluated by "leave-one-out" cross-validation, using a training set of 41 compounds. External validation was performed using a test set of 13 compounds. The obtained  4D-QSAR models are in agreement with the proposed mechanism of action for raloxifene. This study allowed a quantitative prediction of compounds' potency and supported the design of new raloxifene analogs.
Laboratory of Molecular Modeling-LabMMol, Program of Post-Graduation in Chemistry-PPGQu, Institute of Chemistry, Federal University of Rio de Janeiro-UFRJ, Rio de Janeiro 21949-900, RJ, Brazil. acrsodero@gmail.com
Ana Carolina Rennó
AC
Sodero
Nelilma Correia
NC
Romeiro
Elaine Fontes Ferreira
EF
da Cunha
Uiaran
U
de Oliveira Magalhaães
Ricardo Bicca
RB
de Alencastro
Carlos Rangel
CR
Rodrigues
Lúcio Mendes
LM
Cabral
Helena Carla
HC
Castro
Magaly Girão
MG
Albuquerque
D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D020849:Raloxifene Hydrochloride / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry* / Q000494:pharmacology
D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride