Limits...
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.

Scott WL, Alsina J, Audu CO, Babaev E, Cook L, Dage JL, Goodwin LA, Martynow JG, Matosiuk D, Royo M, Smith JG, Strong AT, Wickizer K, Woerly EM, Zhou Z, O'Donnell MJ - J Comb Chem (2009 Jan-Feb)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Indiana University-Purdue University, Indianapolis, Indiana 46202-3274, USA. wscott@iupui.edu

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.

Show MeSH
Representative UV trace from LC/MS analysis of A1 from either resin supplier I or II. (a) LC trace of product (team 1, Al) using resin from supplier I. (b) LC trace of product (team 18, Al) using resin from supplier II.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2651687&req=5

fig2: Representative UV trace from LC/MS analysis of A1 from either resin supplier I or II. (a) LC trace of product (team 1, Al) using resin from supplier I. (b) LC trace of product (team 18, Al) using resin from supplier II.

Mentions: In this first extensive study, two commercial suppliers, I and II, were commissioned to produce the starting benzophenone imine resin 2. For comparison purposes, resin from source I was used in sections one, two, and four (teams 1−8, 10−17, and 26−33), and resin from source II was used in section three (teams 18−25). Since all 32 teams prepared the same product (FmocPhe 5{6}a, see Table 1) in position A1 of their Bill-Boards it was informative to analyze the quality, as a function of resin source, of all 32 of these replicated products. Figure 2 shows a comparison of representative products A1 from teams using resins from these two suppliers.


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.

Scott WL, Alsina J, Audu CO, Babaev E, Cook L, Dage JL, Goodwin LA, Martynow JG, Matosiuk D, Royo M, Smith JG, Strong AT, Wickizer K, Woerly EM, Zhou Z, O'Donnell MJ - J Comb Chem (2009 Jan-Feb)

Representative UV trace from LC/MS analysis of A1 from either resin supplier I or II. (a) LC trace of product (team 1, Al) using resin from supplier I. (b) LC trace of product (team 18, Al) using resin from supplier II.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651687&req=5

fig2: Representative UV trace from LC/MS analysis of A1 from either resin supplier I or II. (a) LC trace of product (team 1, Al) using resin from supplier I. (b) LC trace of product (team 18, Al) using resin from supplier II.
Mentions: In this first extensive study, two commercial suppliers, I and II, were commissioned to produce the starting benzophenone imine resin 2. For comparison purposes, resin from source I was used in sections one, two, and four (teams 1−8, 10−17, and 26−33), and resin from source II was used in section three (teams 18−25). Since all 32 teams prepared the same product (FmocPhe 5{6}a, see Table 1) in position A1 of their Bill-Boards it was informative to analyze the quality, as a function of resin source, of all 32 of these replicated products. Figure 2 shows a comparison of representative products A1 from teams using resins from these two suppliers.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Indiana University-Purdue University, Indianapolis, Indiana 46202-3274, USA. wscott@iupui.edu

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.

Show MeSH