title: Flavanoids as Potential NEDD-4 Inhibitors: In Silico Discovery Using Molecular Docking and ADME Studies.
abstract: NEDD-4 are closely related E3 ubiquitin-protein ligases that include a C2 domain, three or four WW domains and a catalytic HECT ubiquitin ligase domain. The WW domains of NEDD-4 proteins recognize substrates for ubiquitination by binding the sequence L/PPxY (the PY-motif) present in target proteins. NEDD-4 functions as a suppressor of the epithelial Na+ channel (ENaC), which interacts with NEDD-4 WW domains via PY-motifs located at its C-terminus. Fifty compounds, all of them flavanoids, were subjected to molecular docking studies. The chemical structures were built, and docking studies were done using Schrodinger. ADMET studies were also performed. Furthermore, evidence is presented suggesting that interaction between NEDD-4 and the selected compounds from the database may also serve to regulate NEDD-4 stability, as this interaction leads to decreased NEDD-4 self-ubiquitination. Collectively, the studies presented here further our understanding of the substrate specificity and regulation of NEDD-4. We have performed molecular docking and molecular dynamics simulation to study the interactions. The results of molecular dynamics simulation confirmed the binding mode of compounds.
authors.affiliation: Division of Applied Sciences, Indian Institute of Information Technology, Deoghat, Jhalwa, Allahabad, U.P., 211012, India.
authors.forename: Kamal Kumar
authors.initials: KK
authors.lastname: Chaudhary
authors.affiliation: Division of Applied Sciences, Indian Institute of Information Technology, Deoghat, Jhalwa, Allahabad, U.P., 211012, India.
authors.forename: Sarvesh Kumar
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Division of Applied Sciences, Indian Institute of Information Technology, Deoghat, Jhalwa, Allahabad, U.P., 211012, India. nidhimishra@iiita.ac.in.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Mishra
mesh_terms: D000818:Animals; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods*; D056004:Molecular Dynamics Simulation; D000075702:Nedd4 Ubiquitin Protein Ligases; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D005419:Flavonoids; D000075702:Nedd4 Ubiquitin Protein Ligases; D044767:Ubiquitin-Protein Ligases
keywords: ADMET; Molecular docking; Molecular dynamics simulation; NEDD-4