The genesis of high-throughput structure-based drug discovery using protein crystallography

Abstract Over the past 12 years, drugs have been developed using structure-based drug design relying upon traditional crystallographic methods. Established successes, such as the drugs designed against HIV-1 protease and neuraminidase, demonstrate the utility of a structure-based approach in the drug-discovery process. However, the approach has historically lacked throughput and reliability capabilities; these bottlenecks are being overcome by breakthroughs in high-throughput structural biology. Recent technological innovations such as submicroliter high-throughput crystallization, high-performance synchrotron beamlines and rapid binding-site analysis of de novo targets using virtual ligand screening and small molecule co-crystallization have resulted in a significant advance in structure-based drug discovery.