Design principle of heparanase inhibitors: a combined in vitro and in silico study

08 March 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


Heparanase inhibitor
Molecular dynamics simulation
Molecular modeling
Drug discovery

Supplementary materials

Supporting Information
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.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.