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Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies

Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies,10.1016/j.jmgm

Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies   (Citations: 10)
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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 ERα 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, r2=0.93 and q2=0.79; HQSAR, r2=0.92 and q2=0.71; potency models, CoMFA, r2=0.94 and q2=0.72; HQSAR, r2=0.92 and q2=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 ERα modulators having improved affinity and potency.
Journal: Journal of Molecular Graphics & Modelling - J MOL GRAPH MODEL , vol. 26, no. 2, pp. 434-442, 2007
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    • ...More specific mechanisms of interaction between chemicals and ER were described on the basis of Common Reactivity Patterns 28 or comparative molecular field analysis (CoMFA) analysis 22,24 and all of them highlight the importance of steric complementarity and electrostatic interactions between the ligands and the ligand binding pocket (LBP) of the ER...

    E. Mombelli. Evaluation of the OECD (Q)SAR Application Toolbox for the profiling of...

    • ...More specific mechanisms of interaction between chemicals and ER were described on the basis of Common Reactivity Patterns 28 or comparative molecular field analysis (CoMFA) analysis 22,24 and all of them highlight the importance of steric complementarity and electrostatic interactions between the ligands and the ligand binding pocket (LBP) of the ER...

    E. Mombelli. Evaluation of the OECD (Q)SAR Application Toolbox for the profiling of...

    • ...CoMFA and CoMSIA may be extremely sensitive to molecular alignment rules and overall consistency of the molecular alignment, therefore, the determination of spatial molecular alignment is a crucial step in 3D-QSAR studies, since the analyses are highly dependent on the quality of the alignments [19, 20]...

    Ashutosh Kumaret al. Receptor based 3D-QSAR to identify putative binders of Mycobacterium t...

    • ...As an illustrative example of the integration of QSAR strategies, a study with a large series of flavanoids, dihydrobenzoxathiins and dihydrobenzodithiins as estrogen receptor (ER) modulators demonstrated that HQSAR and CoMFA (comparative molecular field analysis) studies can be carried out concomitantly to search for synergies between 2D and 3D QSAR technologies [21]...

    Lívia B. Salumet al. Fragment-based QSAR: perspectives in drug design

    • ...A more recent study using CoMFA and HQSAR methods by sybyl platform was conducted on a series of ERα modulators, producing useful information for design of novel ERαligands [19]...

    Yonghua Wanget al. Prediction of binding affinity for estrogen receptor α modulators usin...

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