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Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3.

ABSTRACT: Numerous studies have highlighted the implications of the glycogen synthase kinase 3 (GSK-3) in several processes associated with Alzheimer's disease (AD). Therefore, GSK-3 has become a crucial therapeutic target for the treatment of this neurodegenerative disorder. Hereby, we report the design and multistep synthesis of ethyl 4-oxo-pyrazolo[4,3-d][1-3]triazine-7-carboxylates and their biological evaluation as GSK-3 inhibitors. Molecular modelling studies allow us to develop this new scaffold optimising the chemical structure. Potential binding mode determination in the enzyme and the analysis of the key features in the catalytic site are also described. Furthermore, the ability of pyrazolotriazinones to cross the blood-brain barrier (BBB) was evaluated by passive diffusion and those who showed great GSK-3 inhibition and permeation to the central nervous system (CNS) showed neuroprotective properties against tau hyperphosphorylation in a cell-based model. These new brain permeable pyrazolotriazinones may be used for key in vivo studies and may be considered as new leads for further optimisation for the treatment of AD.

SUBMITTER: Sciu ML

PROVIDER: S-EPMC6211276 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3.

Sciú M Lourdes ML Sebastián-Pérez Victor V Martinez-Gonzalez Loreto L Benitez Rocio R Perez Daniel I DI Pérez Concepción C Campillo Nuria E NE Martinez Ana A Martinez Ana A Moyano E Laura EL

Journal of enzyme inhibition and medicinal chemistry 20191201 1

Numerous studies have highlighted the implications of the glycogen synthase kinase 3 (GSK-3) in several processes associated with Alzheimer's disease (AD). Therefore, GSK-3 has become a crucial therapeutic target for the treatment of this neurodegenerative disorder. Hereby, we report the design and multistep synthesis of ethyl 4-oxo-pyrazolo[4,3-d][1-3]triazine-7-carboxylates and their biological evaluation as GSK-3 inhibitors. Molecular modelling studies allow us to develop this new scaffold op ...[more]

PMID: 30362380

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Project description:Recent data indicates limited awareness and compliance on infection prevention procedures by dental offices and by dental laboratories. Guidelines for infection prevention in dentistry have been published by Centres for Disease Control and Prevention since 2003; the section "IX-Special consideration" includes a subsection concerning the prevention in dental laboratories, but it has not been modernised in later versions to fit the needs of traditional and computer-aided technology. Traditional techniques required disinfecting items (impression, chewing waxes, and appliances) with well-suited products, which are also chosen for limiting impression changes or appliance deterioration. Effective procedures are available with difficulties. Some of these contain irritant or non-eco-friendly disinfectants. The transport of impression, to dental laboratories, is often delayed with limited precautions for limiting cross-infection. Gypsum casts are frequently contaminated mainly by bacteria and their antibiotic-resistant strains and even stored for long periods during dental implant supported restoration and orthodontic therapy, becoming a hidden source of infection. Nowadays, computer-aided design/computer-aided manufacturing technology seems to be an interesting way to promote both business and safety, being more comfortable for patients and more accurate than traditional technology. A further advantage is easier infection prevention since, for the most part, mainly digital impression and casts are not a source of cross-infection and the transport of contaminated items is reduced and limited to try-in stages. Nevertheless, a peculiar feature is that a digital electronic file is of course unalterable, but may be ruined by a computer virus. Additionally, the reconditioning of scanner tips is determinant for the optical characteristics and long term use of the scanner, but information for its reconditioning from producers is often limited. This study focuses on some critical points including (a) insufficient guidelines, (b) choice of proper procedure for scanner reconditioning, and (c) data protection in relation to patient privacy.

Dataset Information

Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3.

Publications

Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3.

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