Combinatorial computer technology is being dispersed in myriad venues, from companies that specialize in combinatorial chemistry software to companies that act as drug-discovery "partners," providing consulting and lead discovery services, to pharmaceutical companies that in turn develop their own in-house combinatorial software, which they may or may not commercialize.

The relationships between these companies are becoming increasingly complex with the evolution of the industry, and increasing numbers of partnerships between companies blur the lines of distinction.

Some companies, like MDL Information Systems (San Leandro, Calif.), Oxford Molecular (Campbell, Calif.), Molecular Simulations Inc. (MSI, San Diego), and Tripos (St. Louis) sell a wide variety of molecular-modeling software, including extensive combinatorial systems. Others, like Afferent Systems (San Francisco) focus exclusively on combinatorial-chemistry software, such as that for library generation.

Companies like ArQule (Medford, Mass.) and Combichem (San Diego) act as consultants or drug-discovery partners, providing screening and ibrary design services. Longtime software developer Chemical Design (Chipping Norton, England) also markets extensive combinatorial software.

Meanwhile, some pharmaceutical companies like AxyS Pharmaceuticals (South San Francisco) or Vertex Pharmaceuticals (Cambridge, Mass.) have developed their own computational methods for combinatorial chemistry. AxyS is in the process of commercializing its combinatorial technology and already has collaborative agreements with pharmaceutical giant Pharmacia & Upjohn.

Frequently, drug companies have been forming loose partnerships with companies that produce combinatorial software and libraries-Glaxo Wellcome and Oxford Molecular, for example-where the two companies can more freely share information such as drug databases, or software successes.

A recent surprise was the announcement last February by the pharmaceutical company Pharmacopeia (Princeton, N.J.) of an agreement to acquire MSI for about $140 million. One advantage to the pending acquisition, said one Pharmacopeia scientist, is that the mix of software availability with actual pharmaceutical synthesis will allow greater opportunities to test software predictions against experiment, known in the field as "validation."

Pharmacopeia has about 4 million compounds with biological data for many of them, added Scott Kahn, director of life sciences marketing at MSI. "The nice part about joining with Pharmacopeia is the ability to have a partner that is encouraged to provide us access to data, and let us do validation studies. That bodes well for improving the accuracy of our tools," he said.

At the exposition in Dallas, companies discussed their latest contributions to the combinatorial software arena. Chemical Computing Group (Montreal) described three combinatorial software products: QuaSAR-Binary TM, QuaSAR-Cluster, and QuaSAR-CombiDesign. QuaSAR-Binary is designed to swiftly analyze large amounts of data generated during high-throughput screening experiments. The program makes predictions about biological activity of chemical compounds.

QuaSAR-CombiDesign is a library design package that selects diverse collections of molecules. QuaSAR-Cluster uses clustering methods to determine molecular similarity. Molecular similarity software, which helps to identify groups of promising compounds or takes a promising lead compound and generates similar compounds around it, is a feature offered by several companies- Oxford's Asp program, for example, and software from Daylight Chemical Information Systems (Los Altos, Calif.).

Scott Hutton, vice president and general manger for Tripos' discovery software business unit, described a new version of Tripos' UNITY chemical database system for high-throughput screening, which now has the ability to do what's known as partial-match 3-D searching. "The key thing we've recently solved is the ability to test potential binding ligands to see if they partially match," Hutton said.

Meanwhile, MDL is in the process of designing a reagent selector, a product scheduled for release this fall. Reagent Selector will save combinatorial, medicinal, and synthetic chemists much of the classifying and filtering labor that currently accompanies the preparation of lists of synthesis reagents, explained Kara Andrews, strategic marketing director for MDL.

And in library design and generation, Afferent Systems offers combinatorial library software that creates virtual molecules for a database by virtually reacting precursor molecules and selecting those that could be synthesized in the real world, according to Afferent President David Chapman.

ArQule offers clients the ability to produce two types of libraries. The first, a general screening array called Mapping Array, helps companies search for potential drug candidates. Once a candidate has been identified, the companies move on to the Directed Array program, which helps further develop the potential lead compounds.

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