Fully Automated and Rapid Flexible Docking of Inhibitors Covalently Bound to Serine Proteases

摘要

Viral serine proteases have become increasingly attactive targets for rational drug design. Many known inhibitors of serine proteases form a covalent bond to the activated serine oxygen, an interaction not taken into account by available docking software used for database mining. We describe a new method for the fully automated and rapid flexible docking of inhibitors covalently bound to serine proteases. The method combines an energy function specifically tuned for molecular docking and an evolutionary programming search engine, and takes advantage of the constained geometry about the site of covalent attachment to dramatically limit the search space and increase search efficiency. Results for several test systems are presented, including a database search which yielded a known inhibitor as a highranking compound.