Artificial Intelligence–Enabled De Novo Design of Novel Compounds that Are Synthesizable

Abstract

Development of computer-aided de novo design methods to discover novel compounds in a speedy manner to treat human diseases has been of interest to drug discovery scientists for the past three decades. In the beginning, the efforts were mostly concentrated to generate molecules that fit the active site of the target protein by sequential building of a molecule atom-by-atom and/or group-by-group while exploring all possible conformations to optimize binding interactions with the target protein. In recent years, deep learning approaches are applied to generate molecules that are iteratively optimized against a binding hypothesis (to optimize potency) and predictive models of drug-likeness (to optimize properties). Synthesizability of molecules generated by these de novo methods remains a challenge. This review will focus on the recent development of synthetic planning methods that are suitable for enhancing synthesizability of molecules designed by de novo methods.