Abstract
Comparative molecular field analysis (CoMFA) was performed on a series of 47 compounds as potent selective human β3-adrenoceptor (AR) agonists. Low energy conformation of the most active compound in the chosen series was found by Molecular dynamics simulated annealing method. The statistically significant model was established from 33 molecules, which were validated by evaluation of test set of 14 compounds. The fit atom based alignment yielded best predictive CoMFA model (r2 cv=0.583, r2 cnv=0.992, F Value=534.974, SEE=0.074, r2 pred=0.743 with six components). The contour maps obtained from 3D-QSAR studies were appraised for the activity trends of the molecules analyzed. The results indicate that the steric, electrostatic substituents play significant role in β3-AR activity and potency of these compounds. The data generated from the present study can be used as putative pharmacophore in the design of novel, potent, human β3-adrenoceptor agonists as anti-obesity and anti-diabetic agents.
Highlights
The β3-adrenergic receptor (β3-AR)[1] is a G-protein-coupled seven trans membrane domain receptor that is expressed mainly in adipose tissue where the excess fats are stored.[2]
Statistical analysis The Comparative molecular field analysis (CoMFA) model-I developed using 30 compounds in the training set, which exhibited to highest r2cv value of 0.670 and non-cross validated r2ncv value of 0.993 with minimum standard error (0.069) and optimum number of component (6). It led to the development of a new CoMFA model with steric (0.540) and electrostatic (0.460) contributions exhibited superior statistical parameters are shown in the equation
The CoMFA model-II selected for the analysis employed 33 compounds in the training set with a r2cv value of 0.583 and non-cross validated r2ncv value of 0.993, with minimum standard error (0.074) and optimum number of components (6)
Summary
The β3-adrenergic receptor (β3-AR)[1] is a G-protein-coupled seven trans membrane domain receptor that is expressed mainly in adipose tissue where the excess fats are stored.[2] The β3-AR plays a major role in mediating lipolysis in white adipocyte tissue (WAT) and thermogenesis (energy expenditure) in brown adipocyte tissue (BAT).[3] It was found that stimulation of β3-AR by selective agonists produced remarkable anti-obesity effects.[3,4] β3-AR agonists have been found to cause insulin sensitisation.[5,6] A set of lead compounds identified for β3-AR agonistic activity are given in scheme 1.5-9 All the developed new chemical entities for β3-AR produced significant effect in rodents but failed to produce similar effects in humans This has been attributed to the differences in the amino acid sequences and active sites of β3-ARs of humans and animals.[10] The efficacy of these agents towards β1 and β2-ARs has been found to be a liability. Current research in this area is mainly focused on developing selective human β3-AR agonists for producing anti-obesity as well as anti-diabetic effects.[11]
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