Next Article in Journal
NIR Spectroscopic Properties of Aqueous Acids Solutions
Next Article in Special Issue
Prediction of Acute Mammalian Toxicity Using QSAR Methods: A Case Study of Sulfur Mustard and Its Breakdown Products
Previous Article in Journal
A Monoclonal Antibody-Based ELISA for Multiresidue Determination of Avermectins in Milk
Previous Article in Special Issue
A QSAR Study of Environmental Estrogens Based on a Novel Variable Selection Method
Molecules 2012, 17(6), 7415-7439; doi:10.3390/molecules17067415
Article

Application of 4D-QSAR Studies to a Series of Raloxifene Analogs and Design of Potential Selective Estrogen Receptor Modulators

1,2,* , 1,3, 4, 2,5, 1, 2, 5, 6 and 1,*
Received: 12 April 2012 / Revised: 4 June 2012 / Accepted: 5 June 2012 / Published: 15 June 2012
(This article belongs to the Special Issue QSAR and Its Applications)
Download PDF [753 KB, 18 June 2014; original version 18 June 2014]

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.
Keywords: four dimensional quantitative structure-activity relationship (4D-QSAR); ligand based drug design (LBDD); molecular modeling; estrogen receptor alpha (ERa); estrogen receptor beta (ERb); selective estrogen receptor modulator (SERM); raloxifene; ligand binding domain (LBD) four dimensional quantitative structure-activity relationship (4D-QSAR); ligand based drug design (LBDD); molecular modeling; estrogen receptor alpha (ERa); estrogen receptor beta (ERb); selective estrogen receptor modulator (SERM); raloxifene; ligand binding domain (LBD)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Share & Cite This Article

Further Mendeley | CiteULike
Export to BibTeX |
EndNote
MDPI and ACS Style

Sodero, A.C.R.; Romeiro, N.C.; da Cunha, E.F.F.; de Oliveira Magalhães, U.; de Alencastro, R.B.; Rodrigues, C.R.; Cabral, L.M.; Castro, H.C.; Albuquerque, M.G. Application of 4D-QSAR Studies to a Series of Raloxifene Analogs and Design of Potential Selective Estrogen Receptor Modulators. Molecules 2012, 17, 7415-7439.

View more citation formats

Related Articles

Article Metrics

For more information on the journal, click here

Comments

Cited By

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert