Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study

Sankhe, Runali and Rathi, Ekta and Manandhar, Suman and Kumar, Avinash and Pai, Sreedhara Ranganath K and Kini, Suvarna G and Kishore, Anoop (2021) Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study. Journal of Molecular Structure, 1224. pp. 1-13. ISSN 0022-2860

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Abstract

Neprilysin (NEP) is a neutral endopeptidase with diverse physiological roles in the body. NEP’s role in degradation of diverse classes of peptides such as amyloid beta, natriuretic peptide, substance P, angiotensin, endothelins, etc., is associated with pathologies of alzheimer’s, kidney and heart diseases, obesity, diabetes and certain malignancies. Hence, the functional inhibition of NEP in the above systems can be a good therapeutic target. In the present study, in-silico drug repurposing approach was used to identify NEP inhibitors. Molecular docking was carried out using GLIDE tool. 2934 drugs from the ZINC12 database were screened using high throughput virtual screening (HTVS) followed by standard precision (SP) and extra precision (XP) docking. Based on the XP docking score and ligand interaction, the top 8 hits were subjected to free ligand binding energy calculation, to filter out 4 hits (ZINC000000001427, ZINC000001533877, ZINC000000601283, and ZINC000003831594). Further, induced fit docking-standard precision (IFD-SP) and molecular dynamics (MD) studies were performed. The results obtained from MD studies suggest that ZINC000000601283-NEP and ZINC000003831594-NEP complexes were most stable for 20ns simulation period as compared to ZINC000001533877-NEP and ZINC000000001427-NEP complexes. Interestingly, ZINC000000601283 and ZINC000003831594 showed similarity in binding with the reported NEP inhibitor sacubitrilat. Findings from this study suggest that ZINC000000601283 and ZINC000003831594 may act as NEP inhibitors. In future studies, the role of ZINC000000601283 and ZINC000003831594 in NEP inhibition should be tested in biological systems to evaluate therapeutic effect in NEP associated pathological conditions.

Item Type: Article
Uncontrolled Keywords: Neprilysin; inhibitors; drug repurposing; virtual screening; molecular dynamics; molecular docking.
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 01 Jun 2021 10:28
Last Modified: 01 Jun 2021 10:28
URI: http://eprints.manipal.edu/id/eprint/156653

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