Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies Lı ´via de B. Salum, Igor Polikarpov, Adriano D. Andricopulo * Laborato ´rio de Quı ´mica Medicinal e Computacional, Centro de Biotecnologia Molecular Estrutural, Instituto de Fı ´sica de Sa ˜o Carlos, Universidade de Sa ˜o Paulo, Av. Trabalhador Sa ˜o-Carlense 400, 13560-970 Sa ˜o Carlos, SP, Brazil Received 15 December 2006; received in revised form 31 January 2007; accepted 2 February 2007 Available online 8 February 2007 Abstract The estrogen receptor (ER) is an important drug target for the development of novel therapeutic agents for the treatment of breast cancer. Progress towards the design of more potent and selective ER modulators requires the optimization of multiple ligand-receptor interactions. Comparative molecular field analyses (CoMFA) and hologram quantitative structure–activity relationships (HQSAR) were conducted on a large set of ERa modulators. Two training sets containing either 127 or 69 compounds were used to generate QSAR models for in vitro binding affinity and potency, respectively. Significant correlation coefficients (affinity models, CoMFA, r 2 = 0.93 and q 2 = 0.79; HQSAR, r 2 = 0.92 and q 2 = 0.71; potency models, CoMFA, r 2 = 0.94 and q 2 = 0.72; HQSAR, r 2 = 0.92 and q 2 = 0.74) were obtained, indicating the potential of the models for untested compounds. The generated models were validated using external test sets, and the predicted values were in good agreement with the experimental results. The final QSAR models as well as the information gathered from 3D contour maps should be useful for the design of novel ERa modulators having improved affinity and potency. # 2007 Elsevier Inc. All rights reserved. Keywords: Estrogen receptor; Drug design; Breast cancer; CoMFA; HQSAR 1. Introduction Estrogens are crucial endogenous hormones that modulate the development and homeostasis of a wide range of female target tissues, including reproductive tracts, breast and skeletal system [1–3]. Their physiological effects are mediated by the estrogen receptor (ER) subtypes, ERa and ERb, which are members of the nuclear receptor superfamily of ligand-modulated transcrip- tional factors [4–6]. The binding of the natural ligand estradiol or other ligands to ER triggers complex signaling networks, leading to the recruitment of coregulatory complexes and to the transcription or repression of specific genes. The high flexibility of the ER ligand-binding cavity allows the binding of a series of structurally diverse small molecules, which can exhibit agonist and antagonist effects, depending on intrinsic cellular differences in the recruitment of coregulators [1,2,7–11]. The ligand-induced conformational changes in the ER binding site and the receptor structure in general, particularly at the N-terminal helix 12 position and its conformation, are major determinants of either agonist or antagonist properties. The understanding of the molecular recognition process responsible for the pharmacological effects of ER is very complex and has been extensively discussed in the literature [9,12,13]. Given the established role of ERa on the etiology and pathophysiology of breast cancer, the second leading cause of cancer death in women, selective ER modulation is an important strategy in the treatment of this disease [14–16]. The ER modulators tamoxifen (generic) and fulvestrant (Faslodex 1 ) are well-known drugs employed in cancer therapy. Since resistance and serious side effects have been reported, including endometrial changes, hot flashes and irregular menstrual periods, there is an increasing clinical need for new therapeutic agents [2,8,9,16–20]. www.elsevier.com/locate/JMGM Journal of Molecular Graphics and Modelling 26 (2007) 434–442 * Corresponding author. Tel.: +55 16 3373 8095; fax: +55 16 3373 9881. E-mail address: aandrico@if.sc.usp.br (A.D. Andricopulo). 1093-3263/$ – see front matter # 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2007.02.001