Computational modelling of potent β-secretase (BACE1) inhibitors towards Alzheimer's disease treatment

Ugbaja, Samuel C.; Sanusi, Zainab K.; Appiah-Kubi, Patrick; Lawal, Monsurat M.; Kumalo, Hezekiel M.

doi:10.1016/j.bpc.2020.106536

Cited by 19 publications

(28 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We calculate some quantum chemical parameters of these complexes using a density functional theory (DFT) approach. The application of the DFT methods in estimating the chemical reactivity concepts of bioactive metal complexes is relevant. , Studies have shown its uses in calculating electron distribution to explore compounds’ reactivities. − We predict the potentials of these complexes as drug candidates using web-based software. The prediction guided our selection of cytochrome P450 3A4 (CYP3A4) to study the complexes’ inhibitory potency against this enzyme using our own N-layered integrated molecular orbital and molecular mechanics (ONIOM) method.…”

Section: Introductionmentioning

confidence: 99%

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4

et al. 2021

Self Cite

View full text Add to dashboard Cite

We report the synthesis and crystal structures of three new copper(II) Schiff-base complexes. The complexes have been characterized by elemental analysis and Fourier transform infrared (FT-IR) and UV–visible spectroscopies. The X-ray diffraction (XRD) analysis reveals that complexes 1 and 3 crystallize in a monoclinic space group C2/c and 2 in a triclinic space group P1̅, each adopting a square planar geometry around the metal center. We use a density functional theory method to explore the quantum chemical properties of these complexes. The calculation proceeds with the three-dimensional (3D) crystal structure characterization of the complexes in which the calculated IR and UV–vis values are comparable to the experimental results. Charge distribution and molecular orbital analyses enabled quantum chemical property prediction of these complexes. We study the drug-likeness properties and binding potentials of the synthesized complexes. The in silico outcome showed that they could serve as permeability-glycoprotein (P-gp) and different cytochrome P450 substrates. Our calculations showed that the complexes significantly bind to cytochrome P450 3A4.

show abstract

Section: Introductionmentioning

confidence: 99%

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…This approach is fundamentally different from β-secretase inhibition because it does not rely on inhibition but promotion of cleavage. By circumventing inhibition, biologically relevant non-APP sheddase products are not diminished, which could cause less side effects usually reported for β-secretase inhibitors ( 62 ). Another difference is that α-cleavage occurs at the cell surface, which is favorable as drugs must not enter the cell, like β-secretase inhibitors.…”

Section: Discussionmentioning

confidence: 99%

The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by α-secretase ADAM10

Hitschler

Lang

2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…After designing more than 20 substituents ( Figure 3) of different functional units attached in an N‐methylation pattern to the rivastigmine, we use two web‐based software to filter these derivatives. The N‐substitution premise on a recent study [57] where we modified the scissile bond strength of a newly identified beta‐secretase inhibitor [58] for improved affinity. Selective N‐methylation of amide nitrogen atoms increases the proteolytic stability/bioavailability of peptides [59] .…”

Section: Methodsmentioning

confidence: 99%

Tailored Modeling of Rivastigmine Derivatives as Dual Acetylcholinesterase and Butyrylcholinesterase Inhibitors for Alzheimer's Disease Treatment

Adeowo

Oyetunji

Ejalonibu

et al. 2021

Chemistry & Biodiversity

Self Cite

View full text Add to dashboard Cite

Rational modification of known drug candidates to design more potent ones using computational methods has found application in drug design, development, and discovery. Herein, we integrate computational and theoretical methodologies to unveil rivastigmine derivatives as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) for Alzheimer's disease (AD) management. The investigation entails pharmacokinetics screening, density functional theory (DFT) mechanistic study, molecular docking, and molecular dynamics (MD) simulation. We designed over 20 rivastigmine substituents, subject them to some analyses, and identified RL2 with an appreciable blood‐brain barrier score and no permeability glycoprotein binding. The compound shows higher acylation energy and a favored binding affinity to the cholinesterase enzymes. RL2 interacts with the AChE and BuChE active sites showing values of −41.1/−39.5 kcal mol−1 while rivastigmine binds with −32.7/−30.7 kcal mol−1 for these enzymes. The study revealed RL2 (4‐fluorophenyl rivastigmine) as a potential dual inhibitor for AChE and BuChE towards Alzheimer's disorder management.

show abstract

Computational modelling of potent β-secretase (BACE1) inhibitors towards Alzheimer's disease treatment

Cited by 19 publications

References 84 publications

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4

The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by α-secretase ADAM10

Tailored Modeling of Rivastigmine Derivatives as Dual Acetylcholinesterase and Butyrylcholinesterase Inhibitors for Alzheimer's Disease Treatment

Contact Info

Product

Resources

About