BPS2026 – Developing novel inhibitors for striatal-enriched tyrosine phosphatase (STEP) using computational methods

Striatal-enriched tyrosine phosphatase (STEP) is a brain-specific phosphatase that negatively regulates synaptic function by dephosphorylating key substrates, including glutamate receptors. Overactivation of STEP has been linked to Alzheimer’s disease, schizophrenia, Fragile X syndrome, and alcohol-induced cognitive impairment. While TC-2153 is a known STEP inhibitor, its high cost underscores the need for more accessible alternatives. For this study, we performed molecular docking using AutoDock Vina to screen ∼2.5 million ZINC ligands against STEP (PDB: 6h8r ). Concurrently, generic de novo ligands were generated using DOCK6. Top-scoring candidates from both approaches were subjected to 250-ns molecular dynamics (MD) simulations using AMBER, followed by molecular mechanics-generalized born surface area (MM-GBSA) binding free-energy analysis. Selected ZINC ligands showed MM-GBSA average binding free energies ranging from -42.7 to -10.5 kcal/mol. De novo ligands reached MM-GBSA average binding free energies as low as -27.5 kcal/mol. TC-2153 showed MM-GBSA average binding free energy of -13.6 kcal/mol. Several candidates exhibited more favorable profiles than the control. Both ZINC-derived and de novo ligands show promise as potential STEP inhibitors. Future work will explore longer MD runs, scaffold optimization, and comparative analysis with related phosphatases, HePTP and PTPRR, which share conserved kinase interaction motif domains and high catalytic homology.