ConCept: de novo design of synthetic receptors for targeted ligands

Abstract

Low-molecular-weight receptors that bind targeted guest molecules have a wide range of potential applications but are difficult to design. This paper describes an evolutionary method for computer-aided design of such receptors that works by linking together chemical components from a user-defined library around a stable conformation of the targeted ligand. The software can operate in three modes: de novo design, in which it builds a wide variety of receptors from small components; macrocycle design, in which it builds homopolymeric macrocycles around the ligand; and elaboration of an existing receptor structure. The top candidates generated by the automatic construction process are further studied with detailed affinity calculations whose validity is supported by prior studies of experimentally characterized host-guest systems. All three modes of operation are illustrated here through the design of novel adenine receptors.