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

A structure-based ligand design method is proposed and tested, The method i s based on stochastic dynamics simulation of multiple copies of molecular b uilding blocks in the presence of a receptor molecule. The molecular buildi ng blocks are assembled into candidate compounds "on the fly" at given inte rvals 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 reconstr uction in a single simulation, a set of candidate compounds that can be bui lt from the building blocks evolves and is dynamically optimized. The metho d was tested by breaking two known flexible human immunodeficiency virus ty pe 1 protease inhibitors into building blocks and reassembling them in the active site of the enzyme, For the inhibitor L700417, a set of conformation s was generated by the calculation. Among these, the original compound was recovered with the lowest energy at the experimentally observed binding sit e and in the correct conformation. For pepstatin, the experimentally observ ed binding mode of the backbone of the inhibitor was reproduced by a calcul ation in which the building blocks corresponding to the side-chain groups w ere omitted. Proteins 1999;36:462-470. (C) 1999 Wiley-Liss, Inc.