Design Principle of Heparanase Inhibitors: A Combined In Vitro and In Silico Study

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.