Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods

ConspectusComputational methods for docking small molecules to proteins are prominent in drug discovery. There are hundreds, if not thousands, of documented examples—and several pertinent cases within our research program. Fifteen years ago, our first docking-guided drug design project yielded nanomolar metalloproteinase inhibitors and illustrated the potential of structure-based drug design. Subsequent applications of docking programs to the design of integrin antagonists, BACE-1 inhibitors, and aminoglycosides binding to bacterial RNA demonstrated that available docking programs needed significant improvement. At that time, docking programs primarily considered flexible ligands and rigid proteins. We demonstrated that accounting for protein flexibility, employing displaceable water molecules, and using ligand-based pharmacophores improved the docking accuracy of existing methods—enabling the design of bioactive molecules. The success prompted the development of our own program, Fitted, implementing all ...