Synthetic and Medicinal Chemistry
- Synthesis of small molecule reference compounds from milligram to multi-gram scale.
- Evaluation of structure-activity relationships (SAR), based on biological assay results, and next step decisions for progressing a project forward.
- Design and synthesis of chemical libraries for hit and lead identification, as well as diversity libraries based on a structural theme.
- Analog synthesis and lead optimization targeting the improvement of potency, physiochemical, and pharmacokinetic properties.
- Synthesis of custom organic reagents and synthetic intermediates.
- Acquisition, isolation, and identification of natural products.
- Design, development, and synthesis of tagged, covalently modifying, and ‘pull-down’ probe molecules.
- Design and synthesis of small molecules conjugated to antigenic proteins for antibody development.
- Verification of the structural identity and purity of samples.
- 1H and 13C NMR with 1D and 2D spectra acquisition and multinuclear capability.
- HPLC and LC/MS (single quadrupole, triple quadrupole and TOF) analysis.
- Normal, chiral and reverse phase chromatography separations on analytical and/or preparative scales.
- High resolution mass spectrometry for accurate mass determination.
Affinity Selection – Mass Spectrometry (AS-MS) screening; a powerful drug discovery tool
Affinity selection-mass spectrometry (AS-MS) screening is a cost efficient, high-throughput, label-free mass spectrometry screening technique. The method uses a 32,000-member mass encoded library to rapidly identify the preferential binding of candidate molecules to immobilized or soluble protein targets, including those that are difficult to screen using traditional HTS approaches. The figure above illustrates the general AS-MS schematic. AS-MS screening is performed utilizing a 96-well plate format with 400 compound mixture in each well (80 total wells) which increases the chemical space that a target can encounter during a screening while concomitantly consuming minimal amounts of target protein. Such methods directly identify bound components by virtue of their molecular weight and therefore, in contrast to biochemical assays that yield a secondary readout of activity, the incidence of false positives based on “bulk effects” and non-specific binding is very low. This AS-MS technique, which couples liquid-chromatography mass spectrometry (LC/TOF-MS) with size-based ultrafiltration separation, is complimentary to traditional biochemical screening assays. This technique will require an independent biochemical assay for functional activity assessment; ligands thus identified can be followed up in cellular or other assays to evaluate phenotype-level effects. Also, affinity selection methods allow potential ligands to query all protein surfaces and not just the “active site,” enabling the discovery of ligands which act through allosteric or orthosteric binding mechanisms.
- An efficient and robust high throughput screening platform to study binding affinity of a 32,000 compound library against a wide array of soluble protein targets.
- Implements ultrafiltration separation for target-ligand complexes to greatly reduce “false positive” hit rates.
- Uses cheminformatic methods to: 1) Provide rank ordering and affinity measurements of bound ligands over a broad range of affinities and 2) remove promiscuous compounds.
- Does not rely on radioactive or fluorescent reporters or enzyme activities, providing: 1) A complementary assay to traditional biochemical and cell-based screening assays and 2) A screening tool for targets not easily amenable to other methods.
Chemistry Consulting for Projects and Grant Applications