Identification of novel human neutrophil elastase inhibitors from dietary phytochemicals using in silico and in vitro studies

Abstract

Human neutrophil elastase (HNE) has been well studied as a therapeutic target for inflammatory diseases for several decades. A variety of small-molecule HNE inhibitors have been well known, and their mode of binding at the active site of the enzyme has been determined, but none of them reached clinical trials except sivelestat. In this study, we intended to identify potent dietary phytochemicals that can target the active site of HNE by employing computational methods and in vitro inhibition assay. Database retrieval and preparation, structure-based virtual screening and molecular docking, rescoring, free energy calculations, adsorption, distribution, metabolism, and excretion (ADME) predictions and an in vitro assay were conducted to propose a collection of biochemically active molecules with the potential for inhibition against HNE. Overall, 167,504 secondary metabolites originating from the plants were docked. Of these, five natural compounds with drug-like properties have shown remarkable docking profiles to HNE. These hit candidates were then examined for validation through an HNE inhibition assay. The results showed that troxerutin (TX) had better binding efficacy with HNE followed by oleuropein, scutellarin, hesperidin and gossypin. These phytochemicals are present in relatively common fruits and vegetables, indicating the potential for safe and affordable inflammatory disease therapy.

Highlights

• Troxerutin shows the highest HNE binding affinity in computational analysis.

• HIS A: 57 is the major contributor to the protein-ligand interaction.

• Flavonoids exhibit binding efficacy against HNE.

• Flavonoids may serve as potent inhibitors for HNE.

Communicated by Ramaswamy H. Sarma

Keywords:

• Human neutrophil elastase
• phytochemicals
• structure-based virtual screening

Acknowledgments

The authors acknowledge the Department of Science and Technology (DST), New Delhi, India for providing financial assistance to Ms. R.Vidhya under DST-PURSE phase II programme (SR/PURSE Phase 2/25 (c) dated January 16, 2018). The authors also thank DST-FIST and UGC-SAP for the facilities provided in the Department of Biochemistry and Biotechnology, Annamalai University for executing the present study. The authors also thank the DBT project (6242-P104/RGCB/PMD/DBT/ADRO/2015) and the Centre for Bioinformatics, Pondicherry University for providing computational facilities. The authors also thank Dr. D. Vinod, Scientist, Schrodinger for his help in performing computational analysis.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

One of the authors Ms. R.Vidhya received financial support in the form of Project Fellow in the Department of Science and Technology (DST)-PURSE, Phase II programme, New Delhi, India.