SAN FRANCISCO—A collaboration to identify and develop drugs for resistant strains of malaria draws on an unusual combination of resources: U.S. Army research from 1946 plus 21st century informatics and lab technology.
The joint work on malaria began about two years ago between Collaborative Drug Discovery Inc., (CDD) and the Department of Chemical Biology and Therapeutics at St. Jude Children's Research Hospital. CDD created a database of over 12,000 molecules from the 61-year-old, two-volume "A Survey of Malaria Drugs," edited by Frederick Y. Wiselogle.
The monograph, which contains tables of data including descriptions, was not available electronically and lacked indexes. But its information is invaluable: animal study results established structure-activity relationships of molecules against malaria by covering compounds' structures plus biochemical activity, including mechanisms of action and toxicity levels.
The information has now been made accessible, says Dr. Barry Bunin, CEO and president of CDD. "CDD has both a free and a paid version, depending upon people's interests, and this historic malaria data is available for anyone via the CDD database." Fees are charged, however, for import and export of data or using private data in secure groups.
Bunin says CDD has communities around other orphan diseases or developing world diseases, including Chagas disease, African sleeping sickness, tuberculosis, and leishmaniasis. Other ventures include a cancer community and a firewall-protected offering for Big Pharma, says Bunin.
Bunin says CDD's technology enables multiple operations with data.
"The first step is getting heterogeneous data into a database. The benefit is you have a permanent record when you're done. The mining is both chemical mining—this is chemically intelligent substructure search and Lipinski calculations—and biological mining for potency, selectivity, and toxicity. The collaborate [function] is what allows you to choose which data you want to keep 100 percent private and which you want to selectively and securely share with individual collaborators or which you want to make open access."
As with other orphan disease studies, St. Jude will also provide public access to the data once a manuscript on the research is finished, says Dr. Kip Guy, chair of the Department of Chemical Biology and Therapeutics. Guy says cheminformatics specialists often prefer St. Jude's bulk file format, though biologists like CDD because of their tools.
Guy says St. Jude has focused on modeling—incorporating varied data to create multidimensional descriptions of chemical space that can be related to disease states. Interesting compounds can then move into the wet lab, where screening methods involve intact malaria parasites.
"Our initial approach was to take approved drugs and literature-reported chemical candidates, compounds of that ilk," to identify chemotypes that would have streamlined re-approval processes. "What we're really hoping is that we will find buried in this data leads that will take us quickly to the clinic," says Guy.
Worldwide attention is limited in working on orphan diseases like malaria, but Guy says his work receives NIH funding. Federal funds also supported the Army's work in the 1940s, and Guy sees the material's longtime inaccessibility as "a tragedy." Now, however, with the information in a usable format, the data have come full circle. "We're providing it back to Walter Reed [Army Medical Center]," says Guy.
