Refinement of Catalyst hypotheses using simplex optimisation

The program HypoOpt in combination with the MSI program citest has been use d to optimise and expand 3D QSAR Catalyst hypotheses using simplex optimisa tion coupled with cross-validation. Three data sets related to angiotensin converting enzyme inhibition, squalene epoxidase inhibition and HIV proteas e inhibition were used to investigate the outcome of hypothesis optimisatio n. Simplex optimisation using leave-one-out cross-validation during the hyp othesis refinement resulted in improved models with respect to predictivity of an external test set. Furthermore, the utilisation of the geometry of t he active site for the HIV protease inhibitors, represented by Catalyst 'ex cluded volume' features, resulted in an optimised hypothesis with improved predictivity compared with the corresponding hypothesis derived without rec eptor information.