A high-throughput platform for crystallography-based fragment screening

项目总结/文摘

Project Summary/Abstract Fragment-based drug discovery (FBDD) is a widely used method in the pharmaceutical industry for the de novo design of molecules that target new drug candidates. FBDD allows a more effective exploration of chemical space with a higher hit rate compared to high-throughput screening, and this can have significant effects in early drug discovery and in the case of challenging or “non-druggable” targets. FBDD has led to around 30 new drugs entering clinical trials and 2 that have entered the market. FBDD can also be used to discover and develop novel molecules for well-validated and important drug targets that already have marketed drugs against them, both for increasing efficacy with lower toxicity as well as creation of new intellectual property for off-patent drugs. Protein x-ray crystallography (PX) is the gold standard for determining the exact 3D location and orientation of a given fragment bound to a drug target. PX can also detect a wider range of binding affinities compared to other biophysical methods for fragment and compound screening and is independent of protein size. However, crystallography is expensive and inefficient for screening a large fragment library due to significant bottlenecks in mass production of crystals for co-crystallization, crystal soaking with fragments, crystal harvesting, X-ray data collection, structure determination and analysis. Complementary biophysical techniques are often used to prescreen for fragments that bind and PX is then used in a second step to determine the exact binding pose of each fragment. Accelero Biostructures is developing a first-to-market, efficient, one-step PX-based fragment library-screening platform that can revolutionize the field by dramatically increasing the efficiency and reducing the cost of developing novel lead molecules for preclinical testing. In Phase I we evaluated a high-density crystallization grid that dramatically increased the efficiency of target-fragment co-crystallization, crystal soaking with fragments and synchrotron- based data collection, leading to a hit rate of ~5% in a single step while simultaneously producing 3D details of protein-fragment interactions. After successfully completing our Phase I aims, we are now moving ahead with our Phase II plan to integrate this experimental technology with a distributed computational crystallography pipeline and data management/informatics backbone that will allow us to efficiently process a large fragment library screen. We will use several druggable and non-druggable oncology targets implicated in various cancers, from our industry and academic customers, as proof-of-concept systems to demonstrate the utility of our overall platform. Our plans are well-aligned with all of NCATS Drug Discovery and Development SBIR topics of interest: “Tools and technologies to enable assaying of compound activity on currently “non- druggable” targets”; “Co-crystallization high-throughput screening techniques”; “Tools and technologies that increase the predictivity or efficiency of medicinal chemistry, biologic or other intervention optimization”; and “Development of high-throughput imaging technologies that focus on making translational research more efficient”.