3D-QSAR and molecular docking studies on substituted isothiazole analogs as inhibitors against MEK-1 kinase

Abstract

MEK-1 and MEK-2 are dual-specificity kinases and important components in the mitogen-activated protein kinase pathway. These enzymes are crucial for normal cell survival and are also expressed in several types of cancers, making them important targets for drug design. We have applied an integrated in silico approach that combines comparative molecular field analysis, comparative molecular similarity indices analysis, and molecular docking to study the structural determinants for the recognition of substituted isothiazole analogs as allosteric inhibitors against MEK-1 kinase. The best 3D-QSAR models for comparative molecular field analysis and comparative molecular similarity indices analysis were selected based on statistical parameters. 3D contour maps suggested that bulky or long-chain substitutions at the X position on the core part decrease the inhibitory activity, and the presence of a hydrogen bond donor substitution enhances the activity. The bulky and electronegative substitutions at the Y position on the core part enhance the activity of the inhibitors. Molecular docking studies reveal a large and hydrophobic pocket that accommodates the Y substitution and a polar pocket that accommodates substitutions on the X position and forms hydrogen bonding interactions with MEK-1 kinase. The results of the 3D-QSAR analysis corroborate with the molecular docking results, and our findings will serve as a basis for further development of better allosteric inhibitors of MEK-1 kinase against several cancers. The overlay of the most active non-ATP competitive MEK-1 kinase inhibitor from the data set on the CoMSIA electrostatic field contour map. Blue contours indicate regions where electropositive groups increase activity, red contours indicate regions where electronegative groups increase activity. The core of the molecules used for the structure superposition is shown in the inset. X and Y represent the location of substitutions on the core. © 2011 John Wiley & Sons A/S.