Distributed Drug Discovery (D3) proposes solving large drug discovery problems by breaking them into smaller units for processing at multiple sites. A key component of the synthetic and computational stages of D3 is the global rehearsal of prospective reagents and their subsequent use in the creation of virtual catalogs of molecules accessible by simple, inexpensive combinatorial chemistry. The first section of this article documents the feasibility of the synthetic component of Distributed Drug Discovery. Twenty-four alkylating agents were rehearsed in the United States, Poland, Russia, and Spain, for their utility in the synthesis of resin-bound unnatural amino acids 1, key intermediates in many combinatorial chemistry procedures. This global reagent rehearsal, coupled to virtual library generation, increases the likelihood that any member of that virtual library can be made. It facilitates the realistic integration of worldwide virtual D3 catalog computational analysis with synthesis. The second part of this article describes the creation of the first virtual D3 catalog. It reports the enumeration of 24 416 acylated unnatural amino acids 5, assembled from lists of either rehearsed or well-precedented alkylating and acylating reagents, and describes how the resulting catalog can be freely accessed, searched, and downloaded by the scientific community.

There continues to be a need for innovative and inexpensive drugs to treat diseases of the developing world. 1,2 It is also important to link academic training and research to critical societal needs. Indiana University-Purdue University Indianapolis (IUPUI) is addressing both these concerns by developing a concept called "Distributed Drug Discovery" (D 3 ). 3 This Perspective describes how D 3 can harness combinatorial chemistry, distributed over multiple academic and industrial locations, to educate students while they perform a key role in the early stages of drug lead discovery for developing world and otherwise neglected diseases. Two other articles in this issue of the Journal of Combinatorial Chemistry present case histories implementing the chemistry component of D 3 . One involves replicated D 3 syntheses in the United States, Poland, Russia, and Spain. 4 The second is an application in which students at IUPUI make analogs of a potential anticancer agent. 5 In this Perspective, D 3 is discussed in three parts: (I) The Concept of D 3 , (II) The Role of Combinatorial Chemistry in D 3 , and (III) Implementation of D 3 .

For the successful implementation of Distributed Drug Discovery (D3) (outlined in the accompanying Perspective), students, in the course of their educational laboratories, must be able to reproducibly make new, high quality, molecules with potential for biological activity. This article reports the successful achievement of this goal. Using previously rehearsed alkylating agents, students in a second semester organic chemistry laboratory performed a solid-phase combinatorial chemistry experiment in which they made 38 new analogs of the most potent member of a class of antimelanoma compounds. All compounds were made in duplicate, purified by silica gel chromatography, and characterized by NMR and LC/MS. As a continuing part of the Distributed Drug Discovery program, a virtual D3 catalog based on this work was then enumerated and is made freely available to the global scientific community.

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