High-Throughput Biocatalysis for Drug Discovery and Development
Jonathan S. Dordick1, Moo-Yeal Lee2, Anand K. Ramasubramanian3, Seok-Joon Kwon4, Bosung Ku4, and Douglas S. Clark5. (1) Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 Eighth Street, Troy, NY 12180, (2) Chemical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, (3) UC - Berkeley, Dept of Chemical Engineering, Berkeley, CA 94720 - 1462, (4) Rensselaer Polytechnic Institute, 110 Eighth Street, Troy, NY 12180, (5) Chemical Engineering, University of California - Berkeley, University of California - Berkeley, 210 Gilman Hall, Berkeley, CA 94720
New and high-throughput biocatalytic technologies and micro- and nanoscale platforms will be necessary to gain access to nature's “warehouse” of structures and functions, and to be able to manipulate the synthesis of these molecules to yield novel compounds and materials for use in the pharmaceutical, chemical, and agrochemical industries. We have advanced several biocatalytic techniques at the micro- and nanoscales for use in drug discovery and development. These approaches involve the combination of enzyme catalysis with human cell-based screening on microarray platforms and serve as the focus of this presentation. In one approach, we have developed synthetic metabolic pathways based on type III polyketide synthases to generate novel natural product analogs with cell antiproliferative activity. In another approach, we have addressed the emerging need to assess potential drug candidate toxicity at early stages of drug development. Specifically, we have developed the Metabolizing Enzyme Toxicology Assay Chip (MetaChip), which combines high-throughput P450 catalysis with 3D cell-based screening on a microscale platform. The MetaChip enables human cell-specific screening of drug candidates and their P450-generated metabolites at speeds commensurate with very early phases of drug development, thereby enabling unsuitable candidates to be eliminated from consideration much earlier in the drug discovery process.