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. 2010 Dec;19(9):1121-1140.
doi: 10.1007/s00044-009-9257-x. Epub 2009 Oct 31.

Comparative 3D QSAR study on β(1)-, β(2)-, and β(3)-adrenoceptor agonists

P Senthil Kumar  1 , Prasad V Bharatam
Affiliations

Comparative 3D QSAR study on β(1)-, β(2)-, and β(3)-adrenoceptor agonists

P Senthil Kumar et al. Med Chem Res. 2010 Dec.

Abstract

A quantitative structure-activity relationship study of tryptamine-based derivatives of β(1)-, β(2)-, and β(3)-adrenoceptor agonists was conducted using comparative molecular field analysis (CoMFA). Correlation coefficients (cross-validated r(2)) of 0.578, 0.595, and 0.558 were obtained for the three subtypes, respectively, in three different CoMFA models. All three CoMFA models have different steric and electrostatic contributions, implying different requirements inside the binding cavity. The CoMFA coefficient contour plots of the three models and comparisons among these plots provide clues regarding the main chemical features responsible for the biological activity variations and also result in predictions which correlate very well with the observed biological activity. Based on the analysis, a summary regeospecific description of the requirements for improving β-adrenoceptor subtype selectivity is given.

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Figures

Scheme 1
Scheme 1
Essential pharmacophore elements present in β3-AR agonists, as identified from the reported β3-selective arylethonolamine/aryloxypropanolamine derivatives
Fig. 1
Fig. 1
The 3D alignment of the 27 molecules is shown by capped sticks without hydrogens
Fig. 2
Fig. 2
Molecule 4 with atoms used for superimposition are named 1 to 7
Fig. 3
Fig. 3
A graph of experimental vs. predicted activities of the training-set and test-set molecules as β1-AR (a), β2-AR (b), and β3-AR (c) agonists. (formula image) Training set; (formula image) test set
Fig. 4
Fig. 4
CoMFA steric STDEV*COEFF contour plots of the tryptamine-based derivative training set generated for the β1 (a), β2 (b), and β3 (c) models. Compounds 16 (a, c) and 20 (b) are shown inside the field
Fig. 5
Fig. 5
CoMFA electrostatic STDEV*COEFF contour plots of the tryptamine-based derivative training set generated for the β1 (a), β2 (b), and β3 (c) models. Compounds 16 (a, c) and 20 (b) are shown inside the field
Scheme 2
Scheme 2
Proposed hypothetical receptor model of β-Ars binding site
See this image and copyright information in PMC

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