BPS2026 – Early study and discovery of hematopoietic protein tyrosine phosphatase (He-PTP) inhibitors using computational chemistry

Overexpression of hematopoietic protein tyrosine phosphatases (He-PTP) is correlated with acute myeloid leukemia (AML), a common form of cancer with a five-year survival rate under 30%. He-PTP dephosphorylates a T cell signaling site, rendering it inactive. He-PTP contains a catalytic cysteine and a WPD loop that regulates access to the active site. The WPD loop can be targeted by an allosteric inhibitor that could lead to a decrease in the amount of defective T cells, thus lowering the harm done by AML. There is a known inhibitor of He-PTP’s active site, ML199, but it is not safe for human consumption nor easily manufacturable. Targeting the WPD loop allows smaller, lead-like ligands with clean reactivity to inhibit the function of He-PTP. Through the use of computational methods, such as molecular docking and molecular dynamics, the process of finding an effective inhibitor can be expedited and made more financially viable. We have docked 2.5 million lead-like, clean reacting, in stock ZINC ligands with readily available 3D structures, to this WPD loop and have simulated the top 25 at 500 ns in triplicate at 310K and 1 atm. We have analyzed these top simulations and found MM-GBSA values near -30 kcal/mol, supported by RMSD and RMSF. Looking at the bonding interactions in simulation, we have seen that some of these ligands hydrogen bond to the WPD loop and the supporting mechanistic residues. The synthesizability and druggability metrics are promising.