Combinatorial libraries - Combinatorial Chemistry and Chemical Biology
The Combinatorial Chemistry and Chemical Biology Shared Resource has been providing OBOC/OB2C combinatorial libraries, and support services to Cancer Center members. The “one-bead one-compound” (OBOC) and the “one-bead-two-compound” (OB2C) methods are highly efficient, both in compound synthesis and in library screening. Indeed, they are the ultra-high throughput methods unmatched by any parallel synthesis methods. Many UC Davis investigators have developed successful grant proposals using these methods.
In addition to OBOC and OB2C libraries, the Combinatorial Chemistry and Chemical Biology Shared Resource has been providing solution-phase small molecule libraries to Cancer Center investigators.
One-bead-one and -two-compound (OBOC/OB2C) combinatorial libraries
Dr. Kit S. Lam is the inventor of the one-bead one-compound (OBOC) combinatorial library method. The OBOC library method is a powerful tool to discover ligands against various biological targets, such as protein kinase substrates and inhibitors, protease substrates and inhibitors, ligands for cell surface receptors, artiﬁcial enzymes, and various ligands for the preparation of affinity column media.
In order to extend its application to discover cell surface acting functional molecules, Dr. Lam and co-workers have recently modiﬁed the OBOC method by adding a known cell-capturing ligand to the surface of every bead in the OBOC library to generate “one-bead-two-compound” (OB2C) combinatorial libraries. Thus, each bead will display on its surface a cell capturing molecule and a random library compound. When live cells are incubated with such an OB2C library, the cell-capturing ligand will direct the cells to attach to the bead surface, resulting in the display of random library molecules in proximity to the cell surface. Some of these library compounds will interact with a cell surface receptor, resulting in speciﬁc biochemical or cellular response, which can be rapidly detected with an appropriate reporter system.
Cell surface receptors play important roles in cellular communications between adjacent cells, between cells and their extracellular microenvironment, and in intracellular signal transduction. Synthetic molecules that target these receptors are useful reagents for studying the biochemical pathways in which they are involved. Some may even be used as lead compounds for the development of new drugs.
Solution-phase small molecule libraries
The technology involves the development of a novel polymer bead grafted with hydrophilic dendritic polymer on the bead surface such that these beads can be used for in situ solution-phase releasable assays. We can place compound-beads in a single small dish containing microbead high-density micro-well arrays for ultrahigh-throughput solution- phase releasable assays. A technician can screen over 100,000 chemical compounds in a few days. More importantly, this OBOC chemical library method is relatively inexpensive and can be adapted to many existing cell-based or biochemical assays commonly used by many of our Cancer Center members.