A 3-D QSAR Study of Catechol-O-Methyltransferase Inhibitors Using CoMFA and CoMSIA

Inhibitors of Catechol-O-Methyltransferase (COMT) play an important role in the treatment of Parkinson's Disease (PD). A new Three-Dimensional Quantitative Structure-Activity Relationship (3-D QSAR) analysis was performed oil 36 previously reported COMT inhibitors employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methodologies to correlate the Molecular fields and percent inhibition values and three predictive models were derived. The CoMFA and CoMSIA models with steric and electrostatic field yielded cross-validated r(cv)(2)s of 0.585 and 0.528, respectively whereas the conventional r(ncv)(2)S Were 0.979 and 0.891. respectively. The CoMSIA model with hydrophobic field exhibited a r(cv)(2) of 0.544 and a r(ncv)(2) of 0.930. The individual inspection of 3-D contours generated from these models helps in understanding the possible region for structural modification of Molecules to improve the inhibitory bioactivity. These 3-D QSAR models are also Useful for designing and predicting novel COMT inhibitors.