Integrative identification of human serpin PAI‐1 inhibitors fromDracaenadragon blood and molecular implications for inhibitor‐induced PAI‐1 allosterism

Abstract

Human plasminogen activator inhibitor-1 (PAI-1) is an important component of the coagulation system and has been recognized as a potential therapeutic target of diverse cardiovascular disorders. Previously, it was found that the extracts from the Chinese medicine Dracaena dragon blood have potent inhibitory activity against PAI-1, but it is unclear which constituents directly participate in the inhibition and how do they regulate PAI-1 at molecular level. Here, we describe an integrated strategy to identify the dragon blood's chemical constituents that can directly target PAI-1. With the strategy, five compounds 1-5 are hit as promising PAI-1 inhibitor candidates, from which three are measured to have high or moderate activity against PAI-1. In particular, the compound 3 is determined to exhibit the highest potency; this value is roughly comparable with the widely used PAI-1 inhibitor Tiplaxtinin. We further examine the molecular effect of compound 3 on PAI-1 conformation at structural level. It is supposed that small-molecule inhibitor regulates the reactive center loop (RCL) of PAI-1 through an allosterism, that is, binding of compound 3 to PAI-1 can allosterically stabilize RCL in latent form, thus promoting PAI-1 conformational conversion from metastable active form to the inactive latent form. Long-term atomistic simulations also demonstrate that removal of compound 3 can destabilize the structured β-stranded conformation of RCL in latent form, although the current simulations are still not sufficient to characterize the full conversion dynamics trajectory.

Chemical Adjustment of Fibrinolysis

“…It is likely to act as a natural PAI-1 inhibitor by incrementally and selectively affecting PAI-1 levels in ER-/PR- breast cancer cells [ 75 ]. A combination of molecular docking, molecular dynamics, and in vitro chromogenic assays was used to identify the Dracaena dragon blood tree chemical constituents directly targeting PAI-1; this also led to the discovery of a compound that does not bind to the active conformation of PAI-1, but rather binds to and stabilizes the latent form [ 76 ].…”