IADE: a system for intelligent automatic design of bioisosteric analogs

Abstract

Abstract IADE, a software system supporting molecular modellers through the automatic design of non-classical bio-isosteric analogs, scaffold hopping and fragment growing, is presented. The program combines sophisticated cheminfor-matics functionalities for constructing novel analogs and fil-tering them based on their drug-likeness and synthetic accessibility using automatic structure-based design capabil-ities: the best candidates are selected according to their simi-larity to the template ligand and to their interactions with the protein binding site. IADE works in an iterative manner, improving the fitness of designed molecules in every gener-ation until structures with optimal properties are identified. The program frees molecular modellers from routine, repeti-tive tasks, allowing them to focus on analysis and evaluation of the automatically designed analogs, considerably enhanc-ing their work efficiency as well as the area of chemical space that can be covered. The performance of IADE is illustrated through a case study of the design of a nonclassical bioisos-teric analog of a farnesyltransferase inhibitor—an analog that has won a recent ‘‘Design a Molecule’ ’ competition