RESUMEN
The Swiss Light Source facilitates fragment-based drug-discovery campaigns for academic and industrial users through the Fast Fragment and Compound Screening (FFCS) software suite. This framework is further enriched by the option to utilize the Smart Digital User (SDU) software for automated data collection across the PXI, PXII and PXIII beamlines. In this work, the newly developed HEIDI webpage (https://heidi.psi.ch) is introduced: a platform crafted using state-of-the-art software architecture and web technologies for sample management of rotational data experiments. The HEIDI webpage features a data-review tab for enhanced result visualization and provides programmatic access through a representational state transfer application programming interface (REST API). The migration of the local FFCS MongoDB instance to the cloud is highlighted and detailed. This transition ensures secure, encrypted and consistently accessible data through a robust and reliable REST API tailored for the FFCS software suite. Collectively, these advancements not only significantly elevate the user experience, but also pave the way for future expansions and improvements in the capabilities of the system.
Asunto(s)
Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Programas Informáticos , Ensayos Analíticos de Alto Rendimiento/métodos , Descubrimiento de Drogas/métodos , Interfaz Usuario-Computador , Bibliotecas de Moléculas Pequeñas , Cristalografía por Rayos X/métodosRESUMEN
Crystallography-based fragment screening is a highly effective technique employed in structure-based drug discovery to expand the range of lead development opportunities. It allows screening and sorting of weakly binding, low molecular mass fragments, which can be developed into larger high-affinity lead compounds. Technical improvements at synchrotron beamlines, design of innovative libraries mapping chemical space efficiently, effective soaking methods and enhanced data analysis have enabled the implementation of high-throughput fragment screening pipelines at multiple synchrotron facilities. This widened access to CBFS beyond the pharma industry has allowed academic users to rapidly screen large quantities of fragment-soaked protein crystals. The positive outcome of a CBFS campaign is a set of structures that present the three-dimensional arrangement of fragment-protein complexes in detail, thereby providing information on the location and the mode of interaction of bound fragments. Through this review, we provide users with a comprehensive guide that sets clear expectations before embarking on a crystallography-based fragment screening campaign. We present a list of essential pre-requirements that must be assessed, including the suitability of your current crystal system for a fragment screening campaign. Furthermore, we extensively discuss the available methodological options, addressing their limitations and providing strategies to overcome them. Additionally, we provide a brief perspective on how to proceed once hits are obtained. Notably, we emphasize the solutions we have implemented for instrumentation and software development within our Fast Fragment and Compound Screening pipeline. We also highlight third-party software options that can be utilized for rapid refinement and hit assessment.
Asunto(s)
Descubrimiento de Drogas , Proteínas , Cristalografía por Rayos X , Suiza , Descubrimiento de Drogas/métodos , Proteínas/química , SincrotronesRESUMEN
Over the last two decades, fragment-based drug discovery (FBDD) has emerged as an effective and efficient method to identify new chemical scaffolds for the development of lead compounds. X-ray crystallography can be used in FBDD as a tool to validate and develop fragments identified as binders by other methods. However, it is also often used with great success as a primary screening technique. In recent years, technological advances at macromolecular crystallography beamlines in terms of instrumentation, beam intensity and robotics have enabled the development of dedicated platforms at synchrotron sources for FBDD using X-ray crystallography. Here, the development of the Fast Fragment and Compound Screening (FFCS) platform, an integrated next-generation pipeline for crystal soaking, handling and data collection which allows crystallography-based screening of protein crystals against hundreds of fragments and compounds, at the Swiss Light Source is reported.