Serial Crystallography for Structure-Based Drug Discovery

Abstract

Rational drug discovery has greatly accelerated the development of safer and more efficacious therapeutics, assisted significantly by insights from experimentally determined 3D structures of ligands in complex with their targets. Serial crystallography (SX) with X-ray free-electron lasers has enabled structural determination using micrometer- or nanometer-size crystals. This technology, applied in the past decade to solve structures of notoriously difficult-to-study drug targets at room temperature, has now been adapted for use in synchrotron radiation facilities. Ultrashort time scales allow time-resolved characterization of dynamic structural changes and pave the road to study the molecular mechanisms by 'molecular movie.' This article summarizes the latest progress in SX technology and deliberates its demanding applications in future structure-based drug discovery.

Keywords: GPCR ligand swapping; X-ray free-electron laser (XFEL); serial femtosecond crystallography; structure-based drug discovery (SBDD); synchrotron-based serial crystallography; time-resolved serial crystallography.