Ligand Docking and Design in a Flexible Receptor Site

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 Sl' 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.