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

Abstract

Highlights Drug repurposing of FDA approved drugs from ZINC 12 database was done using the crystal structure of extracellular domain of human NEP (PDB ID: 5JMY ) The interactions with catalytic triad of HIS583, HIS587 and GLU646 are important for NEP inhibition. Based on XP molecular docking, binding energy, IFD-SP and MD simulation top 4 NEP inhibitors were identified. ZINC000000601283 and ZINC000003831594 were found to be stable during MD simulation and may act as NEP inhibitors.

Modelling the efficacy of Neprilysin from various species in degrading different Amyloid-β peptides: Potential application in therapeutics of Alzheimer’s disease

“…The protein data bank (PDB; https://www.rcsb.org/) was searched with Neprilysin and Amyloid Additionally the reported sequence of human Amyloid β 1-40 was used to construct the 3D structure using the Chimera software [11][12][13] .…”

“…The 3D structure of Aβ peptides were individually docked against the five neprilysin structures (5JMY, 6GID, 4XBH, 6GHX and 1THL) to identify the number of interaction sites through formation of hydrogen bonds using the Chimera software. [11][12][13] The number of interaction sites observed between the 5JMY and Amyloid β 1-40 was taken as the baseline for all further estimations.…”

Broadening COVID-19 Interventions to Drug Innovation: Neprilysin Pathway as a Friend, Foe, or Promising Molecular Target?

“…An FDA-approved ARNI; Entresto (Navartis), which is a combination of a NEPi (Sacubitril) and an Ang II receptor blocker (valsartan) is helpful to treat various heart problems (McMurray et al, 2014;Sauer et al, 2019). Recent reports proposed that this drug can be repurposed to treat COVID-19 (Acanfora et al, 2020a(Acanfora et al, , 2020bGurwitz, 2020;Sankhe et al, 2021).…”

Modelling the Efficacy of Neprilysin from Various Species in Degrading Different Amyloid-β peptides: Potential Application in Development of Therapeutics for Alzheimer’s Disease

“…The following neprilysin and Amyloid β peptides (PDB ID given) were used: 5JMY (Human Neprilysin from Spodoptera frugiperda expression system, 6GID (Human Neprilysin from Komagataella pastoris expression system), 4XBH (Soluble rabbit neprilysin), 6GHX (Bacterial Thermolysin; Geobacillus stearothermophilus), 1THL (Bacterial Thermolysin; Bacillus thermoproteolyticus), 4XFO (Amyloid-forming segment TAVVTN from human Transthyretin), 5TPT (Amyloid Precursor-Like Protein 2 (APLP2) E2 Domain;Human), 3SGP (Amyloid segment of alphaBcrystallin residues 90-100;Human), 2ROZ (Cytoplasmic tail of amyloid precursor protein;Mouse), 2YT1 (Cytoplasmic tail of amyloid precursor protein; Mouse), 4YN0 (Crystal structure of amyloid precursor protein E2 domain; Mouse), 2KJ7 (Rat Islet Amyloid Polypeptide), 1NMJ (Rat Amyloid beta-1-28), 4DBB (Amyloid precursor protein;Rat), 2BFI (Synthetic amyloid fibril), 2ONX (Amyloid cross-beta spines;Yeast) Additionally the reported sequence of human Amyloid β1-40 was used to construct the 3D structure using the Chimera software. [11][12][13] Molecular docking of the 3D structure…”

“…The 3D structure of Aβ peptides were individually docked against the five neprilysin structures (5JMY, 6GID, 4XBH, 6GHX and 1THL) to identify the number of interaction sites through formation of hydrogen bonds using the Chimera software. [11][12][13] The number of interaction sites observed between the 5JMY and Amyloid β1-40 was taken as the baseline for all further estimations.…”