Discovery of two novel hetero-tricyclic lead scaffolds as PDE5A inhibitor: virtual screening, molecular docking and pharmacophore modeling approach

Abstract

Phosphodiesterase 5A enzyme has been the upcoming and promising target in hypertension management. In this research, reported 270 bioactive natural products having antihypertensive potential were selected and docked against PDE5A using vLife MDS 4.6 software. Based on docking score, π-stacking, H-bond and ionic interactions with PDE5A, 82 tricyclic compounds were selected for further study. Protein residue Gln817A was associated in H-boding, Leu804A in ionic interaction whereas Val782A and Phe820A were associated in π-stacking interaction with ligand. In silico docking studies resulted in discovery of oxygen containing naphthofuran and nitrogen and oxygen containing pyrano quinolizine tricyclic lead scaffolds as novel PDE5A inhibitors. Additionally, developed pharmacophore model suggested that one centre of hydrogen bond acceptor, one aromatic centre and two aliphatic centres are minimum pharmacophoric features required in the molecule so as to show sildenafil like activity. The identified lead scaffolds would provide novel platform for drug discovery of bioactive natural products.

Keywords:

• Docking
• pharmacophore modeling
• PDE5A inhibitor
• bioactives
• natural products

Acknowledgements

The authors are thankful to Dr. H. N. More, Principal, Bharati Vidyapeeth College of Pharmacy, Kolhapur, Maharashtra, India for providing facilities for the work.

Disclosure statement

No potential conflict of interest was reported by the authors.