Developing novel inhibitors for Striatal-Enriched Tyrosine Phosphatase (STEP) using computational methods

Dagmawit Kebede
Dr. Brett A. Berke and Dr. Bill Miller (A.T. Still University), Faculty Mentors

Striatal-Enriched Tyrosine Phosphatase (STEP) is a brain-specific phosphatase that negatively regulates synaptic signaling by dephosphorylating neuronal substrates. Overactivation of STEP has been linked to neurological disorders, including Alzheimer’s disease and schizophrenia, making it a promising therapeutic target. Although TC-2153 is a known STEP inhibitor, its high cost and limited accessibility highlight the need for alternative compounds. In this study, computational screening and simulation were used to identify potential STEP inhibitors. Approximately 2.5 million ligands from the ZINC database were screened against STEP using AutoDock Vina, while de novo ligands were generated and docked with DOCK6, including ongoing efforts to identify potential allosteric binding sites. Top candidates were evaluated using 250 ns molecular dynamics simulations in AMBER and binding free energies were estimated using Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculations. Several ligands showed stronger predicted binding energies than TC-2153, suggesting promising scaffolds for future STEP inhibitor development.

Keywords: Striatal-Enriched Tyrosine Phosphatase, Molecular dynamics, Computational screening, Synaptic signaling regulation

Topic(s):Chemistry
Biochemistry and Molecular Biology
Biology

Presentation Type: Oral Presentation

Session: TBA
Location: TBA
Time: TBA