Small Molecule Libraries Used in the Development of Structure Activity Relationships

Jablonski, Joseph Jack, Department of Chemistry, University of Virginia
Geysen, H. Mario, Department of Chemistry, University of Virginia

With the constant need for the development of new therapeutics, library synthesis has become a staple of modern drug discovery. This technique allows for the synthesis of multiple compounds in parallel to gain insight to activity relationships associated with biological targets. Within this body of work is the development of structure-activity relationships (SAR) at two biologically relevant targets, DPP-IV and NS1.

DPP-IV has been shown to play a critical role in the regulation of incretin hormones responsible for stimulating insulin production. Two known inhibitors of DPPIV (Vildagliptin and Saxagliptin) fall into the class of compounds known as cyanopyrrolidines and display large hydrophobic substituents at either the N-terminus or the α-carbon. Previous SAR studies have examined substitution patterns at the N-terminus, with little attention given to substitution at both the α-carbon and the N-terminus. A 42-compound library was designed to systematically examine steric restrictions within the DPP-IV binding pocket. Additionally, three compounds were synthesized to be used in the development of a functioning assay. Initial work suggested that the substrate Nle-Pro-AMC was participating in substrate inhibition with DPP-IV at concentrations above 50μM. Once this model of analysis was identified, a protocol was developed to screen compounds for biological activity.

The Influenza virus non-structural protein 1 (NS1) is a multifunctional protein which plays a critical role in viral replication. Recent research has identified NS1 as a viable target to treat influenza based on the highly conserved structure across different strains of influenza A and the important cellular interactions which are involved with viral replication. Following a large scale screen, an SAR was developed to design and synthesize novel inhibitors of NS1. Initial studies identified key interactions with the left hand side of the molecule which may play a role in antiviral activity. The resulting compounds were highly potent while exhibiting little cytotoxicity. When amino acids were used as building blocks, antiviral activity was observed for multiple influenza A virus strains. With this result, a 96-compound library was designed and synthesized using 48 different carboxylic acids, amino acids, or dipeptides to further probe essential structural features required for antiviral activity.

PHD (Doctor of Philosophy)
structure-activity relationships, SAR, NS1, Influenza, Library Synthesis, DPP-IV, Diabetes
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