ABSTRACT
The design of novel therapeutic agents based on knowledge of the threedimensional
structure of target proteins has increased significantly in recent years, driven by advances in 3D protein structure determination by highresolution X-ray crystallography and NMR. Moreover, the possibility of linking computational structure-based design technologies (1-3) with func-tional genomics via threading and homology modeling is a tantalizing prospect. With the 3D protein structure in hand, regardless of how it is determined, there are essentially three structure-based design approaches via which we may exploit it. Geometric searching (4, 5) finds molecules that match a set of distance and angular relationships between specific molecular features (a pharmacophore). De novo design (6, 7) constructs molecules directly within the receptor site, either by combining and linking separately docked fragments or by “growing” molecules from a docked anchor fragment. Docking methods fit a small molecule (ligand) into the binding site by optimization of steric, hydrophobic, and electrostatic complementarity in conjunction with an estimate of the corresponding binding free energy (scoring).
