QSAR Analysis on Inhibitors of Human Dihydroorotate Dehydrogenase (hDHODH): The Ary1 Carboxylic Acid Amid Derivatives

Abstract

Structural and physicochemical requirements of aryl carboxylic acid amide derivatives for the inhibition of human dihydroorotate dehydrogenase (hDHODH) are explored in this QSAR study. The calculated molecular descriptors (electronic and thermodynamic) have been used to derive QSAR models between hDHODH inhibitory activity and structural properties. The best model for prediction of hDHODH inhibitory activity is obtained by applying sequential multiple linear regression (SMLR) analysis. Regression coefficient of all the descriptors is significant at more than 99% and statistically significant model with r2 > 0.87 is obtained. Selected QSAR model emphasized the importance of logP, torsion energy (Et), 1,4-dihedral van der Waals interaction (1,4-VDWE) and electronic descriptor like lowest unoccupied molecular orbital (LUMO) on hDHODH inhibitory activity. Results of QSAR analysis show that logP and LUMO are the principle descriptors for inhibition of hDHODH. QSAR model has also been tested successfully for internal (q2 > 0.753) and external (r2 pred > 0.621) validation criteria. It is believed that the results of this study will be helpful in the design of more potent and selective hDHODH inhibitors.