News | June 22, 1999

3-Dimensional Pharmaceuticals Receives Fourth Patent on Pharmaceutical Libraries

3-Dimensional Pharmaceuticals Inc. (3DP; Exton, PA) has received a fourth patent (US Patent 5,901,069) covering the generation of new drug leads through computer-controlled, iterative robotic synthesis and analysis of chemical libraries, a technology 3DP has named DirectedDiversity.

F. Raymond Salemme, president and chief scientific officer at 3DP, noted that the patent extends to any chemical product applications where suitable properties can be measured, including drugs, herbicides, paints, scents, solvents, and advanced materials. DirectedDiversity permits the rapid design and synthesis considered key to developing and refining new drug leads cost-effectively.

DirectedDiversity was developed by 3DP scientists Dimitris K. Agraflotis, Roger F. Bone, F. Raymond Salemme, and Richard M. Soll. 3DP uses DirectedDiversity and other proprietary technologies in its own research and in its collaborations with several other companies, including DuPont, Merck KgaA, Heska Corp., and BioCryst Pharmaceuticals.

Representation of a diverse set of molecules in an accessible library. Each dot represents a molecule in activity space, available from a particular accessible library (in this case containing about 1 billion molecules). Darkly colored data points represent hits.

DirectedDiversity
DirectedDiversity is a computer-aided, iterative process for generating chemical compounds with a prescribed set of physical, chemical, and/or biological properties. Think of it as a way to control the information flow for combinatorial drug discovery and drug property optimization. During each iteration, a chemical library is generated, and the structure and activity of the individual molecules in that library are analyzed to determine how closely they match a desired set of properties. All data pertaining to the structure, properties, and activities of these compounds, both observed and computed, are captured in a database and are then condensed in the form of structure-activity models.

Using information gleaned from past iterations, DirectedDiversity software begins the next cycle by selecting the key compounds, reagents, and synthetic methodologies for the synthesis and evaluation of next-generation compounds. In each successive iteration, existing structure-activity models are refined and new models are constructed, automatically applying the information gained in the previous iterations until the desired compounds have been identified.

DirectedDiversity's computational tools enable discovery scientists to follow up immediately on active "virtual" hits found from screening the probe library, to select additional compounds for structure-activity elaboration. Libraries encode a set of more than 1 million compounds, any of which can be synthesized on demand within two to three weeks of selection using DirectedDiversity chemi-informatics technology.

"DirectedDiversity speeds up the ability of chemists to come up with lead candidates," said Michael Wassil, 3DP's director of business development. "In the past this process was characterized by trial and error. DirectedDiversity gives chemists the ability to access large amounts of chemical structures by computer. When we find something promising based on its medicinal chemistry, we can select it and automatically synthesize it through solid or liquid phase synthesis. It's a form of "just-in-time" synthesis for chemical compounds."

Discovery Programs
3DP is principally involved in two drug discovery programs: protease inhibitors and G-protein coupled receptors. The company's extensive libraries of small, orally active protease inhibitors target antithrombitoc and antimetastatic targets such as thrombin, FXa, and urokinase. 3DP's current protease inhibitor probe libraries incorporate more than 15,000 individually synthesized compounds spanning numerous structural classes.

Discovery work on G-protein coupled receptors (GPCRs) has thusfar been hampered by the inability to produce crystals suitable for 3D X-ray studies. 3DP is developing technology to allow structure determination of GPCRs, complementing its structural work with DirectedDiversity combinatorial library screening. Libraries currently hold 25,000 individually synthesized compounds.

In addition to these two major programs, 3DP is also working on cell surface receptors, integrins, and intracellular signalling targets.

For more information: Michael J. Wassil, Chief Financial Officer, 3-Dimensional Pharmaceuticals, 665 Stockton Drive, Exton, PA 19341. Tel: 610-458-8959. Fax: 610-458-8249.

By Angelo DePalma