Synthesis and anticonvulsant activity of amino acid-derived sulfamides

Sulfamides are promising functions for the design of new antiepileptic drugs (Bioorg. Med. Chem. 2007, 15, 1556-1567; 5604-5614). Following previous research in this line, a set of amino acid-derived sulfamides has been designed, synthesized, and tested as new anticonvulsant compounds. The experimental data confirmed the ability of some of the structures to suppress the convulsions originated by the electrical seizure (MES test) at low doses (100 mg/kg).Fil: Gavernet, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; ArgentinaFil: Elvira, Juan E.. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; ArgentinaFil: Samaja, Gisela Anabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; ArgentinaFil: Pastore, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Cravero, Mariana Sella. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; ArgentinaFil: Enrique, Andrea Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Estiu, Guillermina Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Bruno Blanch, Luis Enrique. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentin

Inhibition pattern of sulfamide-related compounds in binding to carbonic anhydrase isoforms I, II, VII, XII and XIV

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A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination

Identifying Ligand Binding Conformations of the β2-Adrenergic Receptor by Using Its Agonists as Computational Probes

Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β2-adrenergic receptor (β2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β2AR. We show that the select ligands bind preferentially to different predicted conformers of β2AR, and identify a role of β2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. © 2012 Isin et al

Computational Studies of the Cholesterol Transport between NPC2 and the N‑Terminal Domain of NPC1 (NPC1(NTD))

The transport of cholesterol from NPC2 to NPC1 is essential for the maintenance of cholesterol homeostasis in late endosomes. On the basis of a rigid docking model of the crystal structures of the N-terminal cholesterol binding domain of NPC1­(NTD) and the soluble NPC2 protein, models of the NPC1­(NTD)-NPC2-cholesterol complexes at the beginning and the end of the transport as well as the unligated NPC1­(NTD)-NPC2 complex were studied using 86 ns MD simulations. Significant differences in the cholesterol binding mode and the overall structure of the two proteins compared to the crystal structures of the cholesterol binding separate units were obtained. Relevant residues for the binding are identified using MM/GBSA calculations and the influence of the mutations analyzed by modeling them <i>in silico</i>, rationalizing the results of previous mutagenesis experiments. From the calculated energies and the NEB (nudged elastic band) evaluation of the cholesterol transfer mechanism, an atomistic model is proposed of the transfer of cholesterol from NPC2 to NPC1­(NTD) through the formation of an intermediate NPC1­(NTD)-NPC2 complex

Computational Studies of the Cholesterol Transport between NPC2 and the N‑Terminal Domain of NPC1 (NPC1(NTD))

The transport of cholesterol from NPC2 to NPC1 is essential for the maintenance of cholesterol homeostasis in late endosomes. On the basis of a rigid docking model of the crystal structures of the N-terminal cholesterol binding domain of NPC1­(NTD) and the soluble NPC2 protein, models of the NPC1­(NTD)-NPC2-cholesterol complexes at the beginning and the end of the transport as well as the unligated NPC1­(NTD)-NPC2 complex were studied using 86 ns MD simulations. Significant differences in the cholesterol binding mode and the overall structure of the two proteins compared to the crystal structures of the cholesterol binding separate units were obtained. Relevant residues for the binding are identified using MM/GBSA calculations and the influence of the mutations analyzed by modeling them <i>in silico</i>, rationalizing the results of previous mutagenesis experiments. From the calculated energies and the NEB (nudged elastic band) evaluation of the cholesterol transfer mechanism, an atomistic model is proposed of the transfer of cholesterol from NPC2 to NPC1­(NTD) through the formation of an intermediate NPC1­(NTD)-NPC2 complex

Computational Studies of the Cholesterol Transport between NPC2 and the N‑Terminal Domain of NPC1 (NPC1(NTD))

The transport of cholesterol from NPC2 to NPC1 is essential for the maintenance of cholesterol homeostasis in late endosomes. On the basis of a rigid docking model of the crystal structures of the N-terminal cholesterol binding domain of NPC1­(NTD) and the soluble NPC2 protein, models of the NPC1­(NTD)-NPC2-cholesterol complexes at the beginning and the end of the transport as well as the unligated NPC1­(NTD)-NPC2 complex were studied using 86 ns MD simulations. Significant differences in the cholesterol binding mode and the overall structure of the two proteins compared to the crystal structures of the cholesterol binding separate units were obtained. Relevant residues for the binding are identified using MM/GBSA calculations and the influence of the mutations analyzed by modeling them <i>in silico</i>, rationalizing the results of previous mutagenesis experiments. From the calculated energies and the NEB (nudged elastic band) evaluation of the cholesterol transfer mechanism, an atomistic model is proposed of the transfer of cholesterol from NPC2 to NPC1­(NTD) through the formation of an intermediate NPC1­(NTD)-NPC2 complex

Computational Studies of the Cholesterol Transport between NPC2 and the N‑Terminal Domain of NPC1 (NPC1(NTD))

The transport of cholesterol from NPC2 to NPC1 is essential for the maintenance of cholesterol homeostasis in late endosomes. On the basis of a rigid docking model of the crystal structures of the N-terminal cholesterol binding domain of NPC1­(NTD) and the soluble NPC2 protein, models of the NPC1­(NTD)-NPC2-cholesterol complexes at the beginning and the end of the transport as well as the unligated NPC1­(NTD)-NPC2 complex were studied using 86 ns MD simulations. Significant differences in the cholesterol binding mode and the overall structure of the two proteins compared to the crystal structures of the cholesterol binding separate units were obtained. Relevant residues for the binding are identified using MM/GBSA calculations and the influence of the mutations analyzed by modeling them <i>in silico</i>, rationalizing the results of previous mutagenesis experiments. From the calculated energies and the NEB (nudged elastic band) evaluation of the cholesterol transfer mechanism, an atomistic model is proposed of the transfer of cholesterol from NPC2 to NPC1­(NTD) through the formation of an intermediate NPC1­(NTD)-NPC2 complex