Journal of Combinatorial Chemistry 2009-01-01

Distributed Drug Discovery, Part 2: global rehearsal of alkylating agents for the synthesis of resin-bound unnatural amino acids and virtual D(3) catalog construction.

William L Scott, Jordi Alsina, Christopher O Audu, Evgenii Babaev, Linda Cook, Jeffery L Dage, Lawrence A Goodwin, Jacek G Martynow, Dariusz Matosiuk, Miriam Royo, Judith G Smith, Andrew T Strong, Kirk Wickizer, Eric M Woerly, Ziniu Zhou, Martin J O'Donnell

Index: J. Comb. Chem. 11 , 14-33, (2009)

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Abstract

Distributed Drug Discovery (D(3)) 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 D(3) 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 D(3) catalog computational analysis with synthesis. The second part of this article describes the creation of the first virtual D(3) 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.