Automated Microfluidics-Based High Definition Cell Pharmacology Profiling System

DESCRIPTION (provided by applicant): High Throughput Screening (HTS) has evolved into a separate industry, the main goal of which is to discover novel chemical entities with biological activity, hits, which potentially can be further developed into drugs. Together with high throughput combinatorial and parallel synthesis, HTS generates ever growing number of hits, which then are subjected to further characterization of their potencies, efficacies, selectivity, mode of action, etc. All these aspects of the pharmacological profiling of the compounds involve measurements of concentration-dependent responses. New approaches in developing automated systems for such pharmacological profiling are needed to facilitate decision making process in promoting more promising hits for further drug development. This time-consuming and laborious profiling of compounds together with high level of complexity of cell functional responses presents a definite bottleneck in drug discovery process. We suggest solving this bottleneck by developing novel approach in automation of cell-based high throughput pharmacological profiling of small molecules and natural products. With this grant, we propose to develop an economical instrument, which will perform automated high resolution characterization biologically active compounds in three-dimensional space: cell effect vs. ligand concentration vs. time. The micro fluidics of the instrument will allow for miniaturization of cell-based assays and will measure cell responses as a function of both the compound concentration and time after cells stimulation with incremental concentrations of the ligand. Such automated three-dimensional analysis of pharmacological behavior of compounds in miniaturized high throughput format will accelerate assessment of kinetic and mechanistic modes of action of potential drug candidates. This proposal is in response to FOA, PA-06-019 (Molecular Libraries Screening Instrumentation), and is intended "? to develop innovative instrumentation to maximize the efficiency and augment the capabilities of molecular library high throughput screening systems" by substantially facilitating drug development through increased value of pharmacological profiling of hits generated during HTS campaigns. The instrument under development will be easy to integrate into large high throughput screening operations and compatible with chemical genomics and brain receptor research.