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

Molecules

Ana Carolina Rennó Sodero¹  Nelilma Correia Romeiro¹  Elaine Fontes Ferreira da Cunha¹  Uiaran de Oliveira Magalhães¹  Ricardo Bicca de Alencastro¹  Carlos Rangel Rodrigues¹  Lúcio Mendes Cabral¹  Helena Carla Castro¹ 

[1] ¹Laboratory of Molecular Modeling (LabMMol), Program of Post-Graduation in Chemistry (PPGQu), Institute of Chemistry, Federal University of Rio de Janeiro (Universidade Federal do Rio de Janeiro, UFRJ), Rio de Janeiro 21949-900, RJ, Brazil

关键词: 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);   

DOI  :  10.3390/molecules17067415

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.