37th Annual Student Research Conference
Computational Search for Novel HePTP Inhibitors as Therapeutic AML Treatment
Mackenzie E. Sweeney
Dr. Bill R. Miller, Faculty Mentor
Hematopoietic protein tyrosine phosphatase (HePTP) belongs to the kinase interaction motif (KIM) family of phosphatases and negatively regulates T-cell receptor signaling by dephosphorylating downstream signaling molecules. HePTP’s WPD loop, consisting of tryptophan, proline, and aspartic acid residues, adopts an open or closed conformation to regulate substrate access to the active site and could be targeted by small-molecule inhibitors to advance therapeutic treatment of hematopoietic disorders such as acute myeloid leukemia (AML). Efforts to develop selective and membrane-permeable HePTP inhibitors have been complicated by the highly-conserved and positive nature of HePTP’s active site. This project utilized computational methods to screen 3.1 million small-molecule ligands and determine ligand binding efficiency and stability. Three ligands–nicknamed Parker, Austen, and Adichie–demonstrate favorable hydrogen bonding with HePTP residues near the WPD loop, which could hinder enzyme functionality and allosterically inhibit HePTP activity. Further investigation of these compounds may yield novel therapeutic treatments for hematopoietic disorders.
Keywords: protein tyrosine phosphatase, hematopoietic PTP, acute myeloid leukemia, computational, small-molecule inhibitors
Topic(s):Biochemistry and Molecular Biology
Chemistry
Biology
Presentation Type: Oral Presentation
Session: 306-1
Location: MG 2001
Time: 12:45