Development of methods for docking and designing small molecules within the Rosetta code framework

Abstract

Structure-based drug design is a key challenge for pharmaceutical chemists. By studying the structure of proteins bound to natural substrates, researchers can design small molecules which they predict will bind in a similar fashion. Ligand docking software such as RosettaLigand plays a key role in structure-based drug design by predicting how a small molecule and a protein will interact. In this body of research I present improvements to the RosettaLigand docking algorithm. I first demonstrate a strategy for achieving accurate predictions of HIV-1 protease/protease inhibitor binding affinity. Next I present a tutorial for using a new version of RosettaLigand docking code which I wrote. This new version allows simultaneous docking of multiple ligands, docking with interface design, and uses an XML-script interface. The XML interface allows fully customizable ligand docking protocols. Finally I demonstrate simultaneous docking of waters along with small molecule inhibitors within protein interfaces. Water docking improves Rosetta’s ability to predict the structure of the protein/inhibitor interface.