scholarly journals DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

2019 ◽  
Vol 141 (26) ◽  
pp. 10225-10235 ◽  
Author(s):  
Christopher J. Gerry ◽  
Mathias J. Wawer ◽  
Paul A. Clemons ◽  
Stuart L. Schreiber
Keyword(s):  
Small Molecules ◽  
Dna Barcoding ◽  
Complete Matrix

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

2019 ◽  
Author(s):  
Christopher Gerry ◽  
Mathias Wawer ◽  
Paul Clemons ◽  
Stuart Schreiber
Keyword(s):  
Carbonic Anhydrase ◽  
Small Molecules ◽  
Suzuki Reaction ◽  
Structural Diversity ◽  
Similarity Analysis ◽  
Topographic Complexity ◽  
Statistical Framework ◽  
Screening Procedures ◽  
Complete Matrix ◽  
Design Construction

<p></p><p>It is challenging to incorporate stereochemical diversity and topographic complexity into DNA-encoded libraries (DELs) because DEL syntheses cannot fully exploit the capabilities of modern synthetic organic chemistry. Here, we describe the design, construction, and validation of DOS-DEL-1, a library of 107,616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C–H arylation chemistry to furnish complex scaffolds primed for DEL synthesis, and we developed an improved on-DNA Suzuki reaction to maximize library quality. We then studied both the structural diversity of the library and the physicochemical properties of individual compounds using Tanimoto multi-fusion similarity analysis, among other techniques. These analyses revealed not only that most DOS-DEL-1 members have “drug-like” properties, but also that the library more closely resembles compound collections derived from diversity synthesis than those from other sources (<i>e.g.</i>, commercial vendors). Finally, we performed validation screens against horseradish peroxidase and carbonic anhydrase IX, and we developed a novel, Poisson-based statistical framework to analyze the results. A set of assay positives were successfully translated into potent carbonic anhydrase inhibitors (IC<sub>50</sub> = 20.1–68.7 nM), which confirmed the success of the synthesis and screening procedures. These results establish a strategy to synthesize DELs with scaffold-based stereochemical diversity and complexity that does not require the development of novel DNA-compatible chemistry.</p><p></p>

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

2019 ◽  
Author(s):  
Christopher Gerry ◽  
Mathias Wawer ◽  
Paul Clemons ◽  
Stuart Schreiber
Keyword(s):  
Organic Chemistry ◽  
Small Molecules ◽  
Suzuki Reaction ◽  
Similarity Analysis ◽  
Topographic Complexity ◽  
Statistical Framework ◽  
Screening Procedures ◽  
The Impact ◽  
Complete Matrix ◽  
Design Construction

<p></p><p>The syntheses of DNA-encoded libraries (DELs) cannot fully exploit the capabilities of modern synthetic organic chemistry, so it is challenging to incorporate stereochemical diversity and topographic complexity into DEL design. Here, we describe the design, construction, and validation of a library of 107,616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C–H arylation chemistry to furnish complex scaffolds primed for DEL synthesis, and we developed an improved on-DNA Suzuki reaction to maximize library quality. Tanimoto multi-fusion similarity analysis, among other techniques, quantified the impact of synthetic decisions on small-molecule physicochemical properties and library diversity. Validation screens against horseradish peroxidase and carbonic anhydrase IX—analyzed by a novel statistical framework—confirmed the success of the synthesis and screening procedures. These results demonstrate that diverse collections of structurally complex DNA-barcoded compounds may be synthesized without the development of novel DNA-compatible chemistry.</p><p></p>

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

2018 ◽  
Author(s):  
Christopher Gerry ◽  
Mathias Wawer ◽  
Paul Clemons ◽  
Stuart Schreiber
Keyword(s):  
Organic Chemistry ◽  
Horseradish Peroxidase ◽  
Small Molecules ◽  
Similarity Analysis ◽  
Topographic Complexity ◽  
Statistical Framework ◽  
Screening Procedures ◽  
The Impact ◽  
Complete Matrix ◽  
Design Construction

<p>The syntheses of DNA-encoded libraries (DELs) thus far tend to underexploit the capabilities of synthetic organic chemistry, affording compounds of low stereochemical diversity and topographic complexity. Here, we describe the design, construction, and validation of a library of 107,616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C–H arylation chemistry to furnish scaffolds that could be functionalized with known DNA-compatible reactions. We quantified the impact of synthetic decisions on small-molecule physicochemical properties and library diversity <i>via</i> Tanimoto multi-fusion similarity analysis, among other techniques. Test screens against horseradish peroxidase and carbonic anhydrase IX—analyzed by a rigorous statistical framework—confirmed the success of the synthesis and screening procedures. These results demonstrate that diverse collections of structurally complex DNA-barcoded compounds may be synthesized without the development of novel DNA-compatible chemistry.</p>

scholarly journals DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

2019 ◽  
Author(s):  
Christopher Gerry ◽  
Mathias Wawer ◽  
Paul Clemons ◽  
Stuart Schreiber
Keyword(s):  
Carbonic Anhydrase ◽  
Small Molecules ◽  
Suzuki Reaction ◽  
Structural Diversity ◽  
Similarity Analysis ◽  
Topographic Complexity ◽  
Statistical Framework ◽  
Screening Procedures ◽  
Complete Matrix ◽  
Design Construction

<p></p><p>It is challenging to incorporate stereochemical diversity and topographic complexity into DNA-encoded libraries (DELs) because DEL syntheses cannot fully exploit the capabilities of modern synthetic organic chemistry. Here, we describe the design, construction, and validation of DOS-DEL-1, a library of 107,616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C–H arylation chemistry to furnish complex scaffolds primed for DEL synthesis, and we developed an improved on-DNA Suzuki reaction to maximize library quality. We then studied both the structural diversity of the library and the physicochemical properties of individual compounds using Tanimoto multi-fusion similarity analysis, among other techniques. These analyses revealed not only that most DOS-DEL-1 members have “drug-like” properties, but also that the library more closely resembles compound collections derived from diversity synthesis than those from other sources (<i>e.g.</i>, commercial vendors). Finally, we performed validation screens against horseradish peroxidase and carbonic anhydrase IX, and we developed a novel, Poisson-based statistical framework to analyze the results. A set of assay positives were successfully translated into potent carbonic anhydrase inhibitors (IC<sub>50</sub> = 20.1–68.7 nM), which confirmed the success of the synthesis and screening procedures. These results establish a strategy to synthesize DELs with scaffold-based stereochemical diversity and complexity that does not require the development of novel DNA-compatible chemistry.</p><p></p>

Gap junctions in the prothoracic glands of the tobacco hornworm, Manduca sexta

1992 ◽  
Vol 50 (1) ◽  
pp. 706-707
Author(s):  
Ji-da Dai ◽  
M. Joseph Costello ◽  
Lawrence I. Gilbert
Keyword(s):  
Gap Junctions ◽  
Small Molecules ◽  
Manduca Sexta ◽  
Freeze Fracture ◽  
Cell Communication ◽  
Cellular Level ◽  
Thin Sections ◽  
Prothoracic Glands ◽  
Polyhydroxylated Steroids ◽  
Stimulation Of

Insect molting and metamorphosis are elicited by a class of polyhydroxylated steroids, ecdysteroids, that originate in the prothoracic glands (PGs). Prothoracicotropic hormone stimulation of steroidogenesis by the PGs at the cellular level involves both calcium and cAMP. Cell-to-cell communication mediated by gap junctions may play a key role in regulating signal transduction by controlling the transmission of small molecules and ions between adjacent cells. This is the first report of gap junctions in the PGs, the evidence obtained by means of SEM, thin sections and freeze-fracture replicas.

Fusion and Fission Processes in Exocytosis: Possible Roles for Synexin and Osmotic Lysis in the Two Events

1980 ◽  
Vol 38 ◽  
pp. 594-597
Author(s):  
H.B. Pollard ◽  
C.E. Creutz ◽  
C.J. Pazoles ◽  
J.H. Scott
Keyword(s):  
Small Molecules ◽  
Chromaffin Cells ◽  
Adrenal Glands ◽  
General Concept ◽  
Extracellular Calcium ◽  
Large Protein ◽  
Granule Membrane ◽  
Osmotic Lysis ◽  
Per Se ◽  
Chemical Evidence

Exocytosis is a general concept describing secretion of enzymes, hormones and transmitters that are otherwise sequestered in intracellular granules. Chemical evidence for this concept was first gathered from studies on chromaffin cells in perfused adrenal glands, in which it was found that granule contents, including both large protein and small molecules such as adrenaline and ATP, were released together while the granule membrane was retained in the cell. A number of exhaustive reviews of this early work have been published and are summarized in Reference 1. The critical experiments demonstrating the importance of extracellular calcium for exocytosis per se were also first performed in this system (2,3), further indicating the substantial service given by chromaffin cells to those interested in secretory phenomena over the years.

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