ACTIVE-SITE-DIRECTED 3D DATABASE SEARCHING - PHARMACOPHORE EXTRACTIONAND VALIDATION OF HITS

Two new computational tools, PRO_PHARMEX and PRO_SCOPE, for use in act ive-site-directed searching of 3D databases are described. PRO_PHARMEX is a flexible, graphics-based program facilitating the extraction of pharmacophores from the active site of a target macromolecule. These p harmacophores can then be used to search a variety of databases for no vel lead compounds. Such searches can often generate many 'hits' of va rying quality. To aid the user in setting priorities for purchase, syn thesis or testing, PRO_SCOPE can be used to dock molecules rapidly bac k into the active site and to assign them a score using an empirical s coring function correlated to the free energy of binding. To illustrat e how these tools can add value to existing 3D database software, thei r use in the design of novel thrombin inhibitors is described.