A 3‐D QSAR Study of Catechol‐O‐Methyltransferase Inhibitors Using CoMFA and CoMSIA
Chun‐Zhi Ai, Yonghua Wang, Yan Li, Yan Li, Yanhong Li, Yanhong Li, Ling Yang · QSAR & Combinatorial Science · 2008
Abstract 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 on 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‐validatedr$\rm{ _{{\rm{cv}}}^2 }$ sof 0.585 and 0.528, respectively whereas the conventionalr$\rm{ _{{\rm{ncv}}}^2 }$ swere 0.979 and 0.891, respectively. The CoMSIA model with hydrophobic field exhibited ar$\rm{ _{{\rm{cv}}}^2 }$ of 0.544 and ar$\rm{ _{{\rm{ncv}}}^2 }$ 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.