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      Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3β Allosteric Modulators Addressed to Neurodegenerative Diseases

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          Abstract

          Glycogen synthase kinase-3 beta (GSK-3β) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3β allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3β allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3β allosteric modulators.

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          Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density

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            Comparison of simple potential functions for simulating liquid water

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              AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.

              We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique. (c) 2009 Wiley Periodicals, Inc.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                31 July 2021
                August 2021
                : 22
                : 15
                : 8252
                Affiliations
                [1 ]Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto 14040-901, SP, Brazil; suzane.quintana@ 123456usp.br (S.Q.G.); raics@ 123456usp.br (R.C.S.); tomich@ 123456fcfrp.usp.br (C.H.T.P.S.)
                [2 ]Programa de Pós-Graduação em Química Medicinal e Modelagem Molecular, Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém 66075-110, PA, Brazil; keltonbelem@ 123456hotmail.com (K.L.B.S.); breno@ 123456unifap.br (C.B.R.S.)
                [3 ]Laboratório de Modelagem em Química Computacional, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Macapá 68902-280, AP, Brazil
                [4 ]Laboratório Computacional de Química Farmacêutica, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil; leonardobrunofederico@ 123456gmail.com (L.B.F.); isaque.francischini@ 123456usp.br (I.A.G.F.); mpbarcelos@ 123456usp.br (M.P.B.)
                Author notes
                [* ]Correspondence: silvagm@ 123456usp.br (G.M.S.); lqfmed@ 123456gmail.com (R.S.B.)
                Author information
                https://orcid.org/0000-0002-7571-9090
                https://orcid.org/0000-0002-5704-5707
                https://orcid.org/0000-0002-2943-8802
                https://orcid.org/0000-0003-1970-2427
                https://orcid.org/0000-0002-0271-335X
                Article
                ijms-22-08252
                10.3390/ijms22158252
                8348340
                34361017
                cff69a9c-a08a-4c55-abca-bfdbf21b69b1
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 29 April 2021
                : 18 May 2021
                Categories
                Article

                Molecular biology
                neurodegenerative diseases,gsk-3β,allosteric modulators,computer-aided drug design,cavity detection,binding pose,shape similarity,docking

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