Refinement of Catalyst hypotheses using simplex optimisation.

The program HypoOpt in combination with the MSI program citest has been used to optimise and expand 3D QSAR Catalyst hypotheses using simplex optimisation coupled with cross-validation. Three data sets related to angiotensin converting enzyme inhibition, squalene epoxidase inhibition and HIV protease inhibition were used to investigate the outcome of hypothesis optimisation. Simplex optimisation using leave-one-out cross-validation during the hypothesis refinement resulted in improved models with respect to predictivity of an external test set. Furthermore, the utilisation of the geometry of the active site for the HIV protease inhibitors, represented by Catalyst 'excluded volume' features, resulted in an optimised hypothesis with improved predictivity compared with the corresponding hypothesis derived without receptor information.