PRO-LIGAND - AN APPROACH TO DE-NOVO MOLECULAR DESIGN .2. DESIGN OF NOVEL MOLECULES FROM MOLECULAR-FIELD ANALYSIS (MFA) MODELS AND PHARMACOPHORES

A computational approach for molecular design, PRO_LIGAND, has been de veloped within the PROMETHEUS molecular design and simulation system i n order to provide a unified framework for the de novo generation of d iverse molecules which are either similar or complementary to a specif ied target. In this instance, the target is a pharmacophore derived fr om a series of active structures either by a novel interpretation of m olecular field analysis data or by a pharmacophore-mapping procedure b ased on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation proc edures and their abilities are demonstrated by the elucidation of phar macophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophor es.