Macromolecular crystallography from an industrial perspective - the impact of synchrotron radiation on structure-based drug discovery.

Abstract

Structure-based drug design has been an integral part of drug discovery for over three decades, contributing to the development of numerous approved drugs. Here we discuss the evolution, as well as the current state, of structure-based drug design within the pharmaceutical industry, using data from AstraZeneca's internal repository for crystal structures to provide additional context. Over the past 20 years, the company has transitioned from a mixed in-house and synchrotron data collection model to a `synchrotron-only' approach, enabled by technological advancements at synchrotron facilities. We provide real-world examples of structure delivery to projects, including a high-throughput project and a case where a single structure was pivotal for discovering a candidate drug. We conclude that, despite recent developments in single-particle cryo-EM and deep-learning structure prediction methods, macromolecular crystallography remains a critical tool for drug discovery.