Induced Fit Docking (IFD) Study of the Solid State Structure of (2E)-1-(5- bromothiophen-2-yl)-3-[4-(dimethylamino)phenyl]prop-2-en-1-one – Fragment Based Design Approach for Human Aldose Reductase Inhibition

Suresh      B. Vepuri; H.      C. Devarajegowda; S.      Anbazhagan; Y.      Rajendra Prasad

Abstract

Solid state structure information for (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino)phenyl]prop-2-en-1- one is revealed by using single crystal X-ray diffraction study. The conformation of the molecule in solid state is used to carry out the drug design studies like structure optimization by Density Functional Theory (DFT) and Induced Fit Docking (IFD) study on human aldose reductase. The asymmetric unit of (2E)-1-(5-bromothiophen-2-yl)-3-[4- (dimethylamino) phenyl]prop-2-en-1-one, C15H14Br N O S, contains just one molecule. The crystal structure displays intermolecular C11---H11...O3 & C17---H17...O3 hydrogen bonds. Docking experiments were conducted for the crystal structure conformation inside AR active site using Maestro 9.1v. from Schrödinger Suite 2009. GLIDE scoring function was used to calculate the dock score. The co-crystallized inhibitor (IDD594) in X-ray structure of AR-inhibitor complex (PDB id: 1USO) was taken as reference to correlate the results. In docking study the molecule has shown good binding capacity with a dock score of - 9.53891. The negative score for docking experiment signifies favorable positioning of ligand inside AR active site and the value is comparable to that of reference substrate (-10.6841). Results suggested that the molecule can be used as starting point for the development of human aldose reductase inhibitor in fragment based design.

Keywords: Aldose reductase (AR), Solid state structure, Chalcone, Induced Fit, GLIDE, Hydrogen Bond, Halogen Bond, nicotinamide adenine dinucleotide, Na-K-ATPase activity, sorbitol