Structure-based ligand design by dynamically assembling molecular building blocks at binding site

A structure-based ligand design method is proposed and tested. The method is based on stochastic dynamics simulation of multiple copies of molecular building blocks in the presence of a receptor molecule. The molecular building blocks are assembled into candidate compounds "on the fly" at given intervals during the simulation. In the algorithm, a special effort is made to explore different possible combinations of building blocks and to select an optimum combination. By repeating the cycle of deconstruction and reconstruction in a single simulation, a set of candidate compounds that can be built from the building blocks evolves and is dynamically optimized. The method was tested by breaking two known flexible human immunodeficiency virus type 1 protease inhibitors into building blocks and reassembling them in the active site of the enzyme. For the inhibitor L700417, a set of conformations was generated by the calculation. Among these, the original compound was recovered with the lowest energy at the experimentally observed binding site and in the correct conformation. For pepstatin, the experimentally observed binding mode of the backbone of the inhibitor was reproduced by a calculation in which the building blocks corresponding to the side-chain groups were omitted. Proteins 1999;36:462-470.