黃駿翔

Abstract:

In today’s high-cost, high-risk environment of drug development, X-ray protein crystallography (PX) has evolved from a traditional structural validation method into a central driver of drug discovery. This evolution is powered by three converging advances: the emergence of AI tools such as AlphaFold and cryo-electron microscopy (Cryo-EM), which provide accurate structural models and accelerate structure determination; the expansion of chemical libraries to billions of compounds, creating bottlenecks for traditional screening approaches that PX-integrated high-throughput strategies can overcome; and the advancement of synchrotron radiation sources, automation technologies, and high-performance computing, which enable PX at industrial scale.

Modern PX plays a central role in fragment-based drug discovery (FBDD), functioning as a front-line screening platform. It enables the rapid identification of hit compounds and reveals their binding model in high-resolution details, thus offering critical insights to guide lead optimization. Moreover, techniques such as serial synchrotron crystallography (SSX) and serial femtosecond crystallography (SFX) enable the room-temperature structural analysis of dynamic drug-target interactions, thereby enhancing the physiological relevance of the structural data.

At NSRRC, the TPS PX beamlines provide high brilliance, microfocus capabilities, and highly automated workflows, supporting the structural determination of challenging targets and large-scale crystallographic screening. Through real-world industrial examples, including contributions from AstraZeneca, this report demonstrates how PX technology significantly accelerates discovery, reduces development risks, and enables the generation of novel intellectual property. In the AI-driven era of drug development, PX has emerged not only as a structural biology tool but as a strategic asset for pharmaceutical innovation.

Keywords – X-ray Protein Crystallography, Fragment-Based Drug Discovery, Serial Synchrotron Crystallography

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