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- Title
Application of 4D-QSAR Studies to a Series of Raloxifene Analogs and Design of Potential Selective Estrogen Receptor Modulators.
- Authors
Sodero, Ana Carolina Rennó; Romeiro, Nelilma Correia; Da Cunha, Elaine Fontes Ferreira; De Oliveira Magalhães, Uiaran; De Alencastro, Ricardo Bicca; Rodrigues, Carlos Rangel; Cabral, Lúcio Mendes; Castro, Helena Carla; Albuquerque, Magaly Girão
- Abstract
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.
- Subjects
QSAR models; LIGANDS (Biochemistry); COORDINATION compounds; ESTROGEN receptors; RALOXIFENE; LIGAND binding (Biochemistry)
- Publication
Molecules, 2012, Vol 17, Issue 6, p7415
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules17067415