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Abstract
Heparanase (HPSE) is an enzyme responsible for the cleavage of heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs). The enzymatic activity of HPSE contributes to ECM remodeling, regulates growth factors, and its overexpression has been implicated in various types of cancer and inflammation, making it a highly promising therapeutic target. In the last two decades, a number of HPSE inhibitors have been reported by labs worldwide, with most of them belonging to the saccharide-based category. So far, few of the small molecule HPSE inhibitors have progressed into clinical trials and none has gained approval by regulatory agencies, leaving a blank in HPSE drug discovery. Here we present the discovery of a novel HPSE small molecule inhibitor by high-throughput screening using an ultrasensitive HPSE enzymatic activity detecting probe developed in our lab and provide the mechanisms of action behind the HPSE inhibition of the small molecule. By doing a series of molecular dynamics (MD) simulations, we discovered the binding profiles on the derivatives of the lead compound. We summarized the essential structural features of the lead compound to provide insights into the design of future HPSE small molecule inhibitors.
Supplementary materials
Title
Supporting Information
Description
Figure S1 shows the interaction information of 5 small molecules co-crystalized with HPSE.
Figure S2 shows the RMSD of TC LPA5 4 in 500 ns MD simulation with HPSE and the RMSD of protein backbone in 500 ns MD simulation.
Figure S3 shows the binding heatmaps of TC LPA5 4 with HPSE categorized in hydrogen binding, salt bridges, ionic interaction, and hydrophobic interaction.
Figure S4 shows the binding frequency summarized in residues of TC LPA5 4 with HPSE in 500 MD simulation.
Figure S5 shows the RMSD of molecules 1a-1c, 2a-2c, 3a-3b with HPSE in 200 ns MD simulations.
Figure S6 shows the RMSD of molecules 4a-4d, 5a-5e, 6a-6e with HPSE in 200 ns MD simulations.
Spectra 1-13 show the structural information of the synthesized molecules.
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