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      The antidepressant drug paroxetine as a new lead candidate in schistosome drug discovery

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          Abstract

          Paroxetine is a new anti-schistosomal lead with potent activity against schistosomula and adult life stages of S. mansoni.

          Abstract

          Recently, our in silico repositioning-chemogenomics approach predicted paroxetine (PAR), an antidepressant drug, as a inhibitor of Schistosoma mansoni serotonin transporters ( SmSERTs), and consequently, a new anti-schistosomal candidate. With the aim of determining the anti-schistosomal activity of this drug, we initially used a spectrophotometric assay to determine activity against schistosomula worms. During this investigation, we verified that PAR showed a pronounced effect on schistosomula viability (IC 50 = 2.5 μM) after 72 h of incubation. Then, we performed ex vivo studies with adult S. mansoni worms using a new automated image-based assay to accurately measure worm motility. As expected from the PAR's predicted mechanism of action, both male and female worms treated with low concentrations of PAR exhibited enhanced motility followed by reduction in motility as incubation time increased. PAR EC 50 values for motility reduction in male and female worms were 5.1 μM and 9.9 μM after 24 h of exposure, respectively, and this effect was maintained until the end of the experiment (72 h). Lastly, homology modeling and docking studies with SmSERT-A and human SERT ( hSERT) revealed insights into the chemical basis of PAR anti-schistosomal activity. These results provide crucial guidance for further studies to optimize PAR in terms of potency and selectivity.

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          Most cited references35

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          Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules.

          Epik is a computer program for predicting pK(a) values for drug-like molecules. Epik can use this capability in combination with technology for tautomerization to adjust the protonation state of small drug-like molecules to automatically generate one or more of the most probable forms for use in further molecular modeling studies. Many medicinal chemicals can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its solubility and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the molecule, as well as predictions for binding modes and ligand affinities based upon protein-ligand interactions. Despite the importance of the protonation state, many databases of candidate molecules used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like molecules to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pK(a) prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the molecule itself rather just for the particular Lewis structure used on input. In addition, a new iterative technology for generating, ranking and culling the generated protonation states is employed.
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            Integrated Modeling Program, Applied Chemical Theory (IMPACT).

            We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally relevant ligands. As we discuss in this review, explicit solvent simulations have been used to guide our design of implicit solvent models based on the generalized Born framework and a novel nonpolar estimator that have recently been incorporated into the program. With IMPACT it is possible to use several different advanced conformational sampling algorithms based on combining features of molecular dynamics and Monte Carlo simulations. The program includes two specialized molecular mechanics modules: Glide, a high-throughput docking program, and QSite, a mixed quantum mechanics/molecular mechanics module. These modules employ the IMPACT infrastructure as a starting point for the construction of the protein model and assignment of molecular mechanics parameters, but have then been developed to meet specialized objectives with respect to sampling and the energy function. (c) 2005 Wiley Periodicals, Inc.
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              Schistosomiasis.

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                Author and article information

                Journal
                MCCEAY
                MedChemComm
                Med. Chem. Commun.
                Royal Society of Chemistry (RSC)
                2040-2503
                2040-2511
                2016
                2016
                : 7
                : 6
                : 1176-1182
                Affiliations
                [1 ]LabMol – Laboratory for Molecular Modeling and Design
                [2 ]Faculdade de Farmácia
                [3 ]Universidade Federal de Goiás
                [4 ]Goiânia - GO
                [5 ]Brazil
                [6 ]LaBECFar – Laboratório de Bioquímica Experimental e Computacional de Fármacos
                [7 ]Instituto Oswaldo Cruz
                [8 ]Fundação Oswaldo Cruz
                [9 ]Rio de Janeiro - RJ
                [10 ]Imaging Platform, Broad Institute of Massachusetts Institute of Technology and Harvard
                [11 ]Cambridge
                [12 ]USA
                Article
                10.1039/C5MD00596E
                45a951dd-f9b0-4703-9c44-e81d9480c19a
                © 2016
                History

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