Intrinsic protein flexibility is often ignored in the drug discovery process, however, there is increasing evidence suggesting that many therapeutic targets are flexible. In this work, we describe a method for incorporating receptor flexibility, based on protein side-chain rearrangements, in ligand docking and design. The approach is applied to the docking of a highly potent inhibitor in the acetylcholinesterase binding site and to the generation of ligands in the S1' cavity of human collagenase. Simulations are conducted for both static and flexible binding sites and from the results we assess the impact of receptor flexibility in drug discovery procedures.

We describe a combinatorial method for de novo ligand design to an ensemble of receptor structures. Receptor conformations, protonation states, and structural water molecules are considered consistently within the framework of de novo ligand design. The method relies on Monte Carlo optimization to search the space of ligand structures, conformations, and rigid-body movements as well as receptor models. The method is applied to an ensemble of HIV protease and human collagenase receptor models. Ligand structures generated de novo exhibit the correct hydrogen-bonding pattern in the core of the active site, with hydrophobic groups extending into the receptor S1 and S1' pocket space. Furthermore, it is shown that known ligands are recovered in the correct binding mode and in the native, most tightly binding receptor model.