Protein tyrosine phosphatase 1B (PTP1B) is a prominent drug target for numerous diseases including type 2 diabetes, neuroinflammation and various cancers. Despite the focus on developing selective and potent inhibitors of PTP1B for over two decades, no inhibitors have passed beyond stage 2 clinical trials. The PTP family of enzymes is large and diverse, and nearly all contain a highly conserved and charged active site which makes the development of selective and bioavailable drug compounds difficult. However, PTP1B contains an allosteric site ~20A from the active site which shows decreased sequence conservation compared to the active site. Many allosteric inhibitors have been developed to target this allosteric site including the widely studied BBR. Recently a new allosteric inhibitor was discovered which has a significantly different chemical composition. Amorphadiene (AD) is a relatively small hydrocarbon which unexpectedly demonstrates relatively selective binding behavior to PTP1B at the same allosteric site as BBR. Through comparison of the binding and inhibition mechanisms of AD and BBR, we can elude potentially required components of the inhibition mechanism. Using MD simulations, we identify  a set of interactions between the α-3, α-6, and α-7 helices, composing the allosteric binding pocket, which are consistently disrupted with the binding of both ligands. The disruption of these interactions prevents the formation of hydrogen bonds necessary to stabilize the WPD loop in the closed conformation thus, restricting PTP1B in the catalytically inactive form with the WPD loop in the open conformation. Additionally, we observed an inverse relationship between the strength of ligand binding and the flexibility of the α-7 helix which may be a component of the selectivity of the ligands for PTP1B over TCPTP. Overall, this insight into the crucial components of the allosteric mechanism should help the targeted development of more potent and selective allosteric inhibitors.

Determining the mechanism of allosteric inhibition of PTP1B by amorphadiene using  molecular dynamics simulations

ACS Spring 2022

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