Three-dimensional quantitative structure-activity relationships and docking studies of some structurally diverse flavonoids and design of new aldose reductase inhibitors

Abstract

Aldose reductase (AR) plays an important role in the development of several long-term diabetic complications. Inhibition of AR activities is a strategy for controlling complications arising from chronic diabetes. Several AR inhibitors have been reported in the literature. Flavonoid type compounds are shown to have significant AR inhibition. The objective of this study was to perform a computational work to get an idea about structural insight of flavonoid type compounds for developing as well as for searching new flavonoid based AR inhibitors. The data-set comprising 68 flavones along with their pIC50 values ranging from 0.44 to 4.59 have been collected from literature. Structure of all the flavonoids were drawn in Chembiodraw Ultra 11.0, converted into corresponding three-dimensional structure, saved as mole file and then imported to maestro project table. Imported ligands were prepared using LigPrep option of maestro 9.6 version. Three-dimensional quantitative structure-activity relationships and docking studies were performed with appropriate options of maestro 9.6 version installed in HP Z820 workstation with CentOS 6.3 (Linux). A model with partial least squares factor 5, standard deviation 0.2482, R(2) = 0.9502 and variance ratio of regression 122 has been found as the best statistical model.

Keywords: Aldose reductase; designed inhibitor; extra precision glide docking; flavonoids; three-dimensional quantitative structure-activity relationships.

Figure 1

Glucose metabolism in glycolysis and polyol pathway

Figure 2

Structural alignments of all molecules in the data-set

Figure 3

Superimposition of the coligand of 3M0I with it's docked poses computed by extra precision glide (a) without mutation (b) with mutation

Figure 4

Hydrogen bonding interactions: Blue implies positive and orange implies negative effect; 1: Highest active, 54: Lowest active

Figure 5

Hydrophobic interaction: Green implies positive and purple implies negative effect; 1: Highest active, 54: Lowest active

Figure 6

Electron withdrawing effect: Green implies positive and orange implies negative effect; 1: Highest active, 54: Lowest active

Figure 7

Correlation diagram of observed and predicted activity (a: Training set b: Test set)

Figure 8

(a) Two-dimensional ligand interaction diagram of coligand and highest active ligand (b) Two-dimensional ligand interaction diagram of two best designed new molecules

Figure 9

Skeletal structure of flavone