Dataset Information

Computational Study of the Inhibition of RgpB Gingipain, a Promising Target for the Treatment of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease represents one of the most ambitious challenges for biomedical sciences due to the growing number of cases worldwide in the elderly population and the lack of efficient treatments. One of the recent attempts to develop a treatment points to the cysteine protease RgpB as a promising drug target. In this attempt, several small-molecule covalent inhibitors of this enzyme have been proposed. Here, we report a computational study at the atomic level of the inhibition mechanism of the most promising reported compounds. Molecular dynamics simulations were performed on six of them, and their binding energies in the active site of the protein were computed. Contact maps and interaction energies were decomposed by residues to disclose those key interactions with the enzyme. Finally, quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations were performed to evaluate the reaction mechanism by which these drug candidates lead to covalently bound complexes, inhibiting the RgpB protease. The results provide a guide for future re-design of prospective and efficient inhibitors for the treatment of Alzheimer's disease.

SUBMITTER: Movilla S

PROVIDER: S-EPMC10882967 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Computational Study of the Inhibition of RgpB Gingipain, a Promising Target for the Treatment of Alzheimer's Disease.

Movilla Santiago S Martí Sergio S Roca Maite M Moliner Vicent V

Journal of chemical information and modeling 20230117 3

Alzheimer's disease represents one of the most ambitious challenges for biomedical sciences due to the growing number of cases worldwide in the elderly population and the lack of efficient treatments. One of the recent attempts to develop a treatment points to the cysteine protease RgpB as a promising drug target. In this attempt, several small-molecule covalent inhibitors of this enzyme have been proposed. Here, we report a computational study at the atomic level of the inhibition mechanism of ...[more]

PMID: 36648276

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Project description:Human apolipoprotein E (ApoE) is a 299-amino acid secreted glycoprotein that binds cholesterol and phospholipids. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4) and heterozygous carriers of the ε4 allele of the gene encoding ApoE (APOE) have a fourfold greater risk of developing Alzheimer's disease (AD). The enzymes thrombin, cathepsin D, α-chymotrypsin-like serine protease, and high-temperature requirement serine protease A1 are responsible for ApoE proteolytic processing resulting in bioactive C-terminal-truncated fragments that vary depending on ApoE isoforms, brain region, aging, and neural injury. The objectives of the present narrative review were to describe ApoE processing, discussing current hypotheses about the potential role of various ApoE fragments in AD pathophysiology, and reviewing the current development status of different anti-ApoE drugs. The exact mechanism by which APOE gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but APOE is known to directly affect tau-mediated neurodegeneration. ApoE fragments co-localize with neurofibrillary tangles and amyloid β (Aβ) plaques, and may cause neurodegeneration. Among anti-ApoE approaches, a fascinating strategy may be to therapeutically overexpress ApoE2 in APOE ε4/ε4 carriers through vector administration or liposomal delivery systems. Another approach involves reducing ApoE4 expression by intracerebroventricular antisense oligonucleotides that significantly decreased Aβ pathology in transgenic mice. Differences in the proteolytic processing of distinct ApoE isoforms and the use of ApoE fragments as mimetic peptides in AD treatment are also under investigation. Treatment with peptides that mimic the structural and biological properties of native ApoE may reduce Aβ deposition, tau hyperphosphorylation, and glial activation in mouse models of Aβ pathology. Alternative strategies involve the use of ApoE4 structure correctors, passive immunization to target a certain form of ApoE, conversion of the ApoE4 aminoacid sequence into that of ApoE3 or ApoE2, and inhibition of the ApoE-Aβ interaction.

Dataset Information

Computational Study of the Inhibition of RgpB Gingipain, a Promising Target for the Treatment of Alzheimer's Disease.

Publications

Computational Study of the Inhibition of RgpB Gingipain, a Promising Target for the Treatment of Alzheimer's Disease.

Similar Datasets

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