Structure based virtual screening for discovery of novel human neutrophil elastase inhibitors

Abstract

Human neutrophil elastase (HNE) plays an important role in the Chronic Obstructive Pulmonary Disease (COPD) inflammatory process. Over the last few decades HNE inhibitors have been evaluated as potential drug candidates; nevertheless their development was discontinued for various reasons and only sivelestat has been approved for clinical use in Acute Respiratory Distress Syndrome (ARDS). Hence, there is an urgent need for new chemotypes that allow efficient and selective HNE inhibition. With the aim of searching for a new HNE inhibitor we carried out a structure-based virtual screening of the Molecular Operating Environment (MOE) database of drug-like compounds. A commercial library of 653 214 drug-like compounds from different suppliers was docked into the HNE enzyme active site and 28 compounds were selected for purchase and tested. Four new HNE inhibitors in the low micromolar range were identified, displaying selectivity towards HNE when compared with other neutrophil serine proteases. Moreover, the inhibitors 19 and 27 exhibited a non-cytotoxic profile. Compound 19 has shown to be stable toward human plasma and pooled rat microsomal activity whereas ester 27 revealed stability issues toward hydrolytic enzymes. Compounds 19 and 27 appear to be promising leads for further development of HNE inhibitors. This study confirms the extra value of using structure-based chemoinformatic protocols and has successfully identified novel distinct chemotypes for development as new agents against HNE.