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Walters Research Group

The Lead and Probe Discovery Core of the Institute of Therapeutics Discovery and Development

Dr. Michael A. Walters is Director of the Lead and Probe Discovery Core of the ITDD.  The Lead and Probe Discovery Core is a full-service combinatorial chemistry group that specializes in the optimization of compounds that are confirmed as active hits from high-throughput screening.  The process of optimization employed by the LPD features a cycle of design, synthesis, purification, and assay. 

The LPD uses the tools of cheminformatics and the principles of medicinal chemistry to design arrays of follow up compounds based on the structures of the confirmed actives. These arrays help the medicinal chemists in the LPD develop structure-activity and structure-physical property relationships (SAR, SPR) between analogs of the confirmed hits.  These arrays are synthesized using the parallel chemistry equipment available in the LPD.  Compounds are purified in our high-throughput purification group and are made available in plates for screening.  Assay results in the form of SAR and SPR guide subsequent iterations of the optimization cycle, allowing the effective and rapid follow up of multiple active series.

Research

The Walters group is actively involved in several research and development projects:

  1. The discovery of novel small molecules that inhibit the action of Rtt109, a histone transacetylase.
  2. The development of compound libraries design to target receptors with no known ligands.
  3. Support of the goals of the Pilot Scale Libraries work ongoing in the ITDD.  This project provides new, high-value compounds to the Molecular Libraries Small Molecule Repository (MLSMR).  The MLSMR is a cornerstone of the Molecular Libraries Initiative of the NIH, and supplies compounds for screening at the National Screening Centers.
  4. The enumeration of tangible virtual libraries for use in virtual screening.
  5. Discovery of novel inhibitors of PKA (protein kinase A) for use in discerning the biological mechanisms involved in spinocerebellar ataxia.  (Collaboration with Harry Orr (Neuroscience) and Derek Hook (ITDD)