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Neutral endopeptidase or neprilysin (NEP) cleaves the natriuretic peptides, bradykinin, endothelin, angiotensin II, amyloid β protein, substance P, etc., thus modulating their effects on heart, kidney, and other organs. NEP has a proven role in hypertension, heart disease, renal disease, Alzheimer's, diabetes, and some cancers. NEP inhibitor development has been in focus since the US FDA approved a combination therapy of angiotensin II type 1 receptor inhibitor (valsartan) and NEP inhibitor (sacubitril) for use in heart failure. Considering the importance of NEP inhibitors the present work focuses on the designing of a potential lead for NEP inhibition. A structure-based pharmacophore modelling approach was employed to identify NEP inhibitors from the pool of 1140 chemical entities obtained from the ZINC database. Based on the docking score and pivotal interactions, ten molecules were selected and subjected to binding free energy calculations and ADMET predictions. The top two compounds were studied further by molecular dynamics simulations to determine the stability of the ligand-receptor complex. ZINC0000004684268, a phenylalanine derivative, showed affinity and complex stability comparable to sacubitril. However, in silico studies indicated that it may have poor pharmacokinetic parameters. Therefore, the molecule was optimized using bioisosteric replacements, keeping the phenylalanine moiety intact, to obtain five potential lead molecules with an acceptable pharmacokinetic profile. The works thus open up the scope to further corroborate the present in silico findings with the biological analysis.
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http://dx.doi.org/10.1016/j.abb.2024.110019 | DOI Listing |
Free Radic Biol Med
December 2024
Department of Pharmacology, SKLFZCD, (State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Chinese Medicine Guangdong Laboratory, Guangdong, Hengqin, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China. Electronic address:
Mol Cell Biol
December 2024
Applied Oxygen Physiology Project, New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan.
During mammalian development, production sites of the erythroid growth factor erythropoietin (EPO) shift from the neural tissues to the liver in embryos and to the kidneys in adults. Embryonic neural EPO-producing (NEP) cells, a subpopulation of neuroepithelial and neural crest cells, express the gene between embryonic day (E) 8.5 and E11.
View Article and Find Full Text PDFAdv Sci (Weinh)
November 2024
National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, P. R. China.
The phosphorylation of three highly conserved serine residues S23, S24, and S25 (S-S-S motif) has been previously identified in NEP of influenza virus. However, it remains obscure whether and how this motif regulates the vRNPs nuclear export. Here the influenza A H5N6 viruses harboring NEP S23C, S24L, or S25L is generated, allowing to impair the phosphorylation on these sites without mutating viral NS1 protein.
View Article and Find Full Text PDFJ Mol Neurosci
November 2024
School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
It is well known that the development of neurodegeneration, and especially Alzheimer's disease (AD), is often accompanied by impaired olfaction which precedes memory loss. A neuropeptidase neprilysin (NEP)-a principal amyloid-degrading enzyme in the brain-was also shown to be involved in olfactory signalling. Previously we have demonstrated that 5xFAD mice develop olfactory deficit by the age of 6 months which correlated with reduced NEP expression in the brain areas involved in olfactory signalling.
View Article and Find Full Text PDFInt J Mol Sci
October 2024
Faculty of Pharmacy, "Ovidius" University of Constanța, Căpitan Aviator Al. Şerbănescu 6, 900470 Constanța, Romania.
Neuropathic pain (NeP) is a complex and debilitating condition that impacts millions of people globally. Although various treatment options exist, their effectiveness is often limited, and they can be accompanied by significant side effects. In recent years, there has been increasing interest in targeting the N-methyl-D-aspartate receptor (NMDAR) as a potential therapeutic approach to alleviate different types of neuropathic pain.
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