Category: NEWS

Advances in technology have led to a major breakthrough in chemical space exploration. By combining computational and experimental methods, researchers are unlocking the full potential of structure-based drug discovery. One highly regarded approach is Chemical Space Docking, which plays a crucial role in finding promising drug candidates and valuable compounds within vast chemical space. This state-of-the-art method provides a fast and cost-effective way to identify the most relevant compounds, resulting in high hit rates and chemical diversity among hits. [1],[2]

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Fragment-Based Drug Discovery (FBDD) has gained significant attention and importance in recent years as a method for identifying and optimizing hits for drug development. It has led to the development of approved therapeutics and numerous drug candidates, and has enabled the industry to tackle previously considered “undruggable” targets.

FBDD utilizes the benefits of biophysical, biostructural, and biochemical techniques to detect low molecular weight molecules, known as “fragments”, that bind to a target. This approach has several advantages over traditional high-throughput screening, including lower cost, greater chemical diversity, and wider sampling of potential follow-up compounds.

Experts in the field of FBDD will present case studies and the potential of various cutting-edge strategies for successful hit identification and optimization in this talk. Additionally, Dr. Nir London will present how electrophilic fragment screening can speed up the discovery of a new generation of covalent probes for challenging targets. He will also discuss the application of this method for the discovery of the first in-vivo active chemical probe for Pin1 proline isomerase and SARS-CoV-2 main protease.

Several discovery partners will provide key expertise, including 2bind, which offers a comprehensive service package for all types of projects and scientific questions, including fragment libraries, hit identification, hit validation, and biophysical assays for SAR and medicinal chemistry optimization. CrystalsFirst provides a state-of-the-art structural biology platform to unlock chemical matter for pharmaceutical and biotechnology companies in drug discovery. Its unique technology SmartSoak® stabilizes protein crystals for X-ray crystallography, providing rapid access to high-quality co-structures. Oncodesign is an expert in integrated drug discovery services, offering hit to lead optimization starting from identified fragments and full lead optimization with a dedicated multidisciplinary team.

Fragment-based drug discovery (FBDD) has become an indispensable resource for medicinal chemists in searching for lead candidates. To effectively evaluate fragments, various biophysical methods are applied using a cascade approach as a pre-screening step before determining protein-ligand interactions. This approach has been found to be more effective than direct crystallographic screening based on research.

The use of X-ray crystallography as a primary fragment screening method has been limited by the lack of robust systems for soaking experiments and the solubility challenges of fragments. One of the major obstacles in crystal soaking is the sensitivity of protein crystals, but this can be overcome with the SmartSoak® technology, which stabilizes protein crystals to create high-performance soaking systems without any need for trial-and-error optimization.

Our case studies highlight the advantages of using crystallographic fragment screening as the primary screening method for hit identification. The resulting structural data can then be used to explore chemical space on a large scale using computational methods.

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