ACCELERO BIOSTRUCTURES INC — Department of Health and Human Services SBIR Phase I: 100

Description

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 Protein x ray crystallography PX is the gold standard for determining the exact D location and orientation of a given fragment bound to a drug target However crystallography is expensive and inefficient for screening a large fragment library due to significant bottlenecks in crystallization crystal soaking with fragments crystal harvesting X ray data collection structure determination and analysis Complementary 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 an 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 Our Phase I plan is to evaluate a high density crystallization grid which will dramatically increase efficiency of target fragment co crystallization crystal soaking with fragments and synchrotron based data collection Our Phase II plan will include a complete integration of this technology into our overall platform Throughout we will use a previously non druggable target implicated in various cancers as proof of concept Our plans align well with NCATS SBIRandapos s topics of interest Tools and technologies to enable assaying of compound activity on currently non druggable targets and Co crystallization high throughput screening techniques Project Narrative Fragment based drug discovery FBDD is widely used in the pharmaceutical industry to provide novel leads for developing new therapeutics It is based on the principle that small compounds andlt Da molecular weight which bind with low millimolar affinity can serve as useful building blocks for the development of novel lead compounds X ray crystallography is the gold standard for determining the exact binding orientation of a fragment as an essential step in this process However conventional crystallography is inefficient for screening a large fragment library due to expense and effort Due to this complementary techniques such as Surface Plasmon Resonance SPR Thermal Shift Assay TSA or Nuclear Magnetic Resonance NMR are often used to prescreen for fragments that bind while protein crystallography is used in a second step to determine the exact binding pose of each fragment An efficient cost effective crystallography based fragment screen can accelerate the development of lead compounds by directly providing D structures of fragments bound to a target of interest The goal of this proposal is to develop of a high throughput platform for crystallography based fragment screening leveraging a novel high density sample crystallization grid which will require a very small volume of purified protein sample andlt mg In this proposal we will evaluate the novel grid which will eliminate key bottlenecks associated with crystallization produce apo crystals for fragments ligands soaks or co crystallization with fragments ligands crystal mounting and rapid synchrotron data collection In Phase I we will test the grid for all experimental steps including crystallization fragment soaking and data collection In Phase II we will optimize the grid design for FBDD applications In addition we will integrate this technology into the Accelero Biostructures ABSTM platform by further developing informatics and data analysis to efficiently handle large fragment library screens and rapidly provide D fragment bound structures