A branch-and-bound method for optimal atom-type assignment in de novo ligand design.

This paper investigates a computational procedure for the determination of the atom types on the vertices of a molecular skeleton to optimize interaction with the receptor site whilst maintaining a synthetically reasonable structure. The connectivity of the skeleton is analysed and appropriate atom types are compiled for each vertex. Receptor ionization and conformational states are generated by varying the positions of hydrogen atoms and electron lone pairs in the carboxyl, rotatable hydroxyl and amino groups. The structure is divided into small non-overlapping substructures. Atom types are assigned exhaustively onto each of the substructures using a depth-first search method; chemical rules are applied to reject unacceptable atom combinations early on. An empirical interaction score is calculated and the representatives of each partial structure are stored in ascending order according to their scores. The branch-and-bound procedure is then used to find the structures with the lowest scores. The method is illustrated using five protein-ligand complexes.