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      Estudo eletroquímico e químico-quântico da oxidação do antidepressivo tricíclico amitriptilina Translated title: Electrochemical and quantum-chemical studies of the oxidation of the antidepressant amitriptyline

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          Translated abstract

          This work presents the electrochemical and quantum chemical studies of the oxidation of the tricyclic antidepressant amitriptyline (AM) employing a carbon-polyurethane composite electrode (GPU) in a 0.1 mol L-1 BR buffer. The electrochemical results showed that the oxidation of AM occurs irreversibly at potentials close to 830 mV with the loss of one electron and one proton and is controlled by reagent and product adsorption. According to the PM3 results, the atom C16 is the region of highest probability for the oxidation of AM since it has the largest charge variation.

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          Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity.

          Peroxisome Proliferator-Activated Receptor γ (PPARγ) full agonists are molecules with powerful insulin-sensitizing action that are used as antidiabetic drugs. Unfortunately, these compounds also present various side effects. Recent results suggest that effective PPARγ agonists should show a low transactivation activity but a high binding affinity to inhibit phosphorylation at Ser273. We use several structure activity relationship studies of synthetic PPARγ agonists to explore the different binding features of full and partial PPARγ agonists with the aim of differentiating the features needed for binding and those needed for the transactivation activity of PPARγ. Our results suggest that effective partial agonists should have a hydrophobic moiety and an acceptor site with an appropriate conformation to interact with arm II and establish a hydrogen bond with Ser342 or an equivalent residue at arm III. Despite the fact that interactions with arm I increase the binding affinity, this region should be avoided in order to not increase the transactivation activity of potential PPARγ partial agonists.
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            The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrödinger FEP.

            In drug discovery, protonation states and tautomerization are easily overlooked. Through a Merck-Rutgers collaboration, this paper re-examined the initial settings and preparations for the Thermodynamic Integration (TI) calculation in AMBER Free-Energy Workflows, demonstrating the value of careful consideration of ligand protonation and tautomer state. Finally, promising results comparing AMBER TI and Schrödinger FEP+ are shown that should encourage others to explore the value of TI in routine Structure-based Drug Design.
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              Eletroquímica: Princípios, Métodos e Aplicações

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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                qn
                Química Nova
                Quím. Nova
                Sociedade Brasileira de Química (São Paulo )
                1678-7064
                June 2005
                : 28
                : 3
                : 456-461
                Affiliations
                [1 ] Universidade de São Paulo
                [2 ] Universidade Federal de São Carlos Brazil
                [3 ] Universidade de São Paulo
                Article
                S0100-40422005000300017
                10.1590/S0100-40422005000300017
                4b1ad09c-406a-47dd-8113-25892eb93e9b

                http://creativecommons.org/licenses/by/4.0/

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                SciELO Brazil

                Self URI (journal page): http://www.scielo.br/scielo.php?script=sci_serial&pid=0100-4042&lng=en
                Categories
                CHEMISTRY, MULTIDISCIPLINARY

                General chemistry
                amitriptyline,composite electrode,PM3 semi-empirical method
                General chemistry
                amitriptyline, composite electrode, PM3 semi-empirical method

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