Three-dimensional quantitative structure activity relationships (3-D-QSAR)of antihyperglycemic agents

A three-dimensional quantitative structure activity relationship study (3-D -QSAR) was performed on a set of thiazolidinedione antihyperglycemic agents using the comparative molecular field analysis (CoMFA) method. The CoMFA m odels were derived from a training set of 53 compounds. Fifteen compounds, which were not used in model generation were used to validate the CoMFA mod els. All the compounds were superimposed to the template structure by atom- based and shape-based strategies. The SYBYL QSAR rigid body field fit was a lso used for aligning the ligands. A total of twelve different alignments w ere generated. The resulting models exhibited a good cross-validated r(cv)( 2) values (0.624-0.764) and the conventional r(2) values (0.689-0.921). A m ore robust cross-validation test using cross-validation by 2 groups (leave half out method) was performed 100 times to ascertain the predictiveness of the CoMFA models. The mean of r(cv)(2) values from 100 runs ranged from 0. 611-0.690. Few models exhibited good external predictivity. These models we re then used to define a hypothetical receptor model for antihyperglycemic agents. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.