Automated molecular design: a new fragment-joining algorithm

A popular first step in the problem of structure-based, 'de novo' molecule design is to identify regions where specific functional groups or chemical entities would be expected to interact strongly. When the three-dimensional structure of the receptor is not available, it may be possible to derive a pharmacophore giving the three-dimensional relationships between such chemical groups. The task then is to design synthetically feasible molecules which not only contain the required groups, but which can also position them in the desired relative orientation. One way to do this is to first link the groups using an acyclic chain. We have investigated the application of the 'tweak' algorithm [Shenkin, P.S. et al., Biopolymers, 26 (1987) 2053] for generating families of acyclic linkers. These linking structures can subsequently be 'braced' using a ring-joining algorithm [Leach, A.R. and Lewis, R.A., J. Comput. Chem., 15 (1994) 233], giving rise to an even wider variety of molecular skeletons for further studies.