Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors

• Published in: Journal of computer-aided molecular design 2008-10, Vol.22 (10), p.711-725
• Main Authors: Lei, Beilei, Du, Juan, Li, Shuyan, Liu, Huanxiang, Ren, Yueying, Yao, Xiaojun
• Format: Article
• Language: English
• Subjects: Allosteric Site; Animal Anatomy; Biotechnology; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Hepatitis; Hepatitis C virus; Histology; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Inhibitors; Least-Squares Analysis; Models, Molecular; Molecular biology; Molecular Conformation; Molecular Structure; Morphology; Pharmacology; Physical Chemistry; Quantitative Structure-Activity Relationship; Static Electricity; Thiazoles - chemistry; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-008-9230-7

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a series of thiazolone derivatives as novel inhibitors bound to the allosteric site of hepatitis C virus (HCV) NS5B polymerase were developed based on CoMFA and CoMSIA analyses. Two different conformations of the template molecule and the combinations of different CoMSIA field/fields were considered to build predictive CoMFA and CoMSIA models. The CoMFA and CoMSIA models with best predictive ability were obtained by the use of the template conformation from X-ray crystal structures. The best CoMFA and CoMSIA models gave q 2 values of 0.621 and 0.685, and r 2 values of 0.950 and 0.940, respectively for the 51 compounds in the training set. The predictive ability of the two models was also validated by using a test set of 16 compounds which gave r pred 2 values of 0.685 and 0.822, respectively. The information obtained from the CoMFA and CoMSIA 3D contour maps enables the interpretation of their structure-activity relationship and was also used to the design of several new inhibitors with improved activity.