Microfluidic Device for Molecular Binding Assessment and Drug Discovery

SUMMARY ABSTRACT The broad impact of this SBIR phase I project is to develop and commercialize a novel biophysical instrument that will greatly enhance researcherscapability to identify better drug candidates for molecular medicineSignificanceBiophysical analysis of molecular interactions is not only essential for disease related biomedical researchbut has also become increasingly popular for drug developmentespecially in Fragment based Drug Discovery against challenging targets such as protein protein interaction interfacesHowevercurrent biophysical techniquese gSPRITC and fluorescence based methodsoffer only limited throughputand mostly require extra pre treatment stepslabeling or immobilizationthat likely result in signal artifacts and enormous effort on assay optimizationAt presentsignificant tradeoff seems inevitable among the throughputaccuracy and sensitivity when choosing the method of biophysical screeningand the result is a prolonged screening process with likely suboptimal lead compoundwhich increases the chance of failures in downstream drug developmentInnovationWe have developed a new instrument that offers unparalleled speedaccuracy and convenience in molecular interaction analysiswithout the need for labeling or immobilizationIt is based on Transient Induced Molecular Electronic SpectroscopyTIMESa novel technology that records transient electrical signal induced by proteinsconfiguration specific charge distribution which is highly sensitive to ligand bindingThe device also leverages benefits of the microfluidic system and realizes accurate measurement at minimal sample consumption in a high throughput fashionIt is a universal tool for rapid assessment of biomolecular binding affinities regardless of sizestructure or charge statusfitting strong commercial needs from both biophysical labsfor daily protein researchand pharmaceutical industryfor high throughput screeningPreliminary DataWe have demonstrated by using a prototype device that TIMES accurately reproduced affinity values of five classic protein ligand pairs with diverse molecular propertiesSpecific AimsIn Specific Aimwe will optimize the current device design and algorithm to further improve signal to noise ratio and its versatilitySeveral proposed strategies will be tested and optimal improvements will be incorporated in developing a robust commercial prototypeIn Specific Aimwe will demonstrate TIMESapplicability for drug discovery by applying it to high impact protein ligand interaction pairsespecially those for fragment based drug discovery and conformation specific modulatorsand comparing its accuracy and efficiency with existing technologies in parallelIn Specific Aimwe will demonstrate the scalability of TIMES for high throughput settings by constructing a new design with multiplied microfluidic channels and embedded valve system to achieve a sample throughput that is andgttimes higher than current techniquesTogetherthese studies will firmly establish the commercial utility and feasibility of TIMES instrument for both biophysical research and drug discovery NARRATIVE Characterization of interaction affinity between biologically important molecules and disease relevant proteins is critical for understanding causes of diseases and developing new drugsIn order to support such characterizationwe propose to develop a novel technologytermed Transient Induced Molecular Electronic SpectroscopyTIMESwhich enables rapidaccurate and direct measurement of molecule protein binding affinitiesIt will be commercialized into a new instrument that will allow researchers to conduct more efficient research for better drug candidates against challenging disease causing targets