What Is Combinatorial Biocatalysis?

Combinatorial biocatalysis is a technique that exploits the unique properties of biological catalysts to derive specific compounds of virtually any size, and produce libraries of structurally diverse products as individual compounds. We are expanding the scope of our technology to include solid-phase reactions to generate lead compound libraries on solid and soluble polymer platforms. This is a new paradigm for lead optimization that taps into nature's vast biocatalytic repertoire. Solid-phase biocatalysis will be used in a lead optimization process, where enzymes and whole-cell extracts are used to derive lead compounds.

This approach couples the exquisite and controllable selectivity and unique reactivity of biocatalysts with the high-throughput features of solid-phase combinatorial methodologies to provide novel capabilities to chemists, biologists, and engineers in the search for new biologically active molecules. This research represents the first application of using an engineering-based biocatalytic approach to generate diversity in the derivatization of lead compounds, which is often a stumbling block in drug discovery.

Background

The discovery and optimization of new biologically active compounds is a multidisciplinary enterprise encompassing the fields of natural and synthetic products. Many new drugs are obtained from or inspired by plant, marine, and microbial sources. Following initial drug discovery, significant effort is devoted to creating the optimal pharmacological entity for clinical evaluation. Traditional synthesis of new compounds is accomplished for the most part using reliable methods that enable the synthesis of virtually any type of organic compound. However, this typically requires many steps, multiple purifications, and often low yields of products.

Because many proven biologically active compounds are so complex, drug discovery recently has turned to combinatorial techniques for new lead discovery and development. Our goal is to develop the capability to generate large libraries of derivatives that ultimately can be used for in vitro and in vivo screening for pharmacological activity. A broad range of small molecules will be attached to solid resins and soluble polymer supports, and will be used in our initial studies to develop the solid-phase biocatalytic technology.

Model Reactions

Bergenin has been chosen as a model molecule for derivatization. Presence of multiple functional groups on the molecules enables introduction of diversity into the molecule as shown below. Techniques to enable high throughput derivatization of drug molecules is one of the goals of this project.