Human GPR40 receptor, also known as free fatty-acid receptor 1, is a G-protein-coupled
receptor that binds long chain free fatty acids to enhance glucose-dependent insulin secretion. In order
to improve the resistance and efficacy, computational tools were applied to a series of 3-aryl-3-
ethoxypropanoic acid derivatives. A relationship between the structure and biological activity of these
compounds, was derived using a three-dimensional quantitative structure-activity relationship (3DQSAR)
study using CoMFA, CoMSIA and two-dimensional QSAR study using HQSAR methods.
Methods: Building the 3D-QSAR models, CoMFA, CoMSIA and HQSAR were performed using
Sybyl-X software. The ratio of training to test set was kept 70:30. For the generation of 3D-QSAR model
three different alignments were used namely, distill, pharmacophore and docking based alignments.
Molecular docking studies were carried out on designed molecules using the same software.
Results: Among all the three methods used, Distill alignment was found to be reliable and predictive
with good statistical results. The results obtained from CoMFA analysis q2, r2cv and r2
pred were 0.693,
0.69 and 0.992 respectively and in CoMSIA analysis q2, r2cv and r2pred were 0.668, 0.648 and 0.990.
Contour maps of CoMFA (lipophilic and electrostatic), CoMSIA (lipophilic, electrostatic, hydrophobic,
and donor) and HQSAR (positive & negative contribution) provided significant insights i.e. favoured and
disfavoured regions or positive & negative contributing fragments with R1 and R2 substitutions, which
gave hints for the modifications required to design new molecules with improved biological activity.
Conclusion: 3D-QSAR techniques were applied for the first time on the series 3-aryl-3-
ethoxypropanoic acids. All the models (CoMFA, CoMSIA and HQSAR) were found to be satisfactory
according to the statistical parameters. Therefore such a methodology, whereby maximum structural information
(from ligand and biological target) is explored, gives maximum insights into the plausible
protein-ligand interactions and is more likely to provide potential lead candidates has been exemplified
from this study.