Journal Article

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

Albuquerque, Magaly Girão, De Alencastro, Ricardo Bicca, Cabral, Lúcio Mendes, Rodrigues, Carlos Rangel, Da Cunha, Elaine Fontes Ferreira, De Oliveira Magalhães, Uiaran, Castro, Helena Carla, Romeiro, Nelilma Correia, Sodero, Ana Carolina Rennó

2012

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Breast cancer / Cancer therapies / Cardiovascular system / College campuses / estrogen receptor alpha (ERa) / Estrogen Receptor alpha - antagonists & inhibitors / Estrogen Receptor alpha - chemistry / estrogen receptor beta (ERb) / Estrogens / FDA approval / four dimensional quantitative structure-activity relationship (4D-QSAR) / Inhibitory Concentration 50 / Laboratories / ligand based drug design (LBDD) / ligand binding domain (LBD) / Ligands / Molecular Conformation / Molecular Dynamics Simulation / molecular modeling / Osteoporosis / Pharmacy / Prevention / Protein Binding / Quantitative Structure-Activity Relationship / raloxifene / Raloxifene Hydrochloride - analogs & derivatives / Raloxifene Hydrochloride - chemistry / Raloxifene Hydrochloride - pharmacology / selective estrogen receptor modulator (SERM) / Selective Estrogen Receptor Modulators - chemistry / Selective Estrogen Receptor Modulators - pharmacology