29 results on '"Thomas Scior"'
Search Results
2. Five Novel Non-Sialic Acid-Like Scaffolds Inhibit In Vitro H1N1 and H5N2 Neuraminidase Activity of Influenza a Virus
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Thomas Scior, Gerardo Santos-López, Irma Herrera-Camacho, Julio Reyes-Leyva, and Luis Márquez-Domínguez
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viruses ,Pharmaceutical Science ,scaffold hopping ,Ligands ,medicine.disease_cause ,01 natural sciences ,neuraminidase inhibitors ,Analytical Chemistry ,chemistry.chemical_compound ,Influenza A Virus, H1N1 Subtype ,Non-competitive inhibition ,Drug Discovery ,Influenza A virus ,Zanamivir ,Enzyme Inhibitors ,Benzoic acid ,0303 health sciences ,biology ,noncompetitive inhibition ,Benzoic Acid ,Molecular Docking Simulation ,Biochemistry ,Chemistry (miscellaneous) ,ligand docking ,Molecular Medicine ,flu drugs ,Influenza A Virus, H5N2 Subtype ,influenza ,medicine.drug ,Neuraminidase ,010402 general chemistry ,Antiviral Agents ,Binding, Competitive ,Article ,lcsh:QD241-441 ,Structure-Activity Relationship ,03 medical and health sciences ,lcsh:Organic chemistry ,medicine ,Humans ,Physical and Theoretical Chemistry ,IC50 ,030304 developmental biology ,Binding Sites ,Organic Chemistry ,Ascorbic acid ,N-Acetylneuraminic Acid ,0104 chemical sciences ,Sialic acid ,Kinetics ,chemistry ,biology.protein - Abstract
Neuraminidase (NA) of influenza viruses enables the virus to access the cell membrane. It degrades the sialic acid contained in extracellular mucin. Later, it is responsible for releasing newly formed virions from the membrane of infected cells. Both processes become key functions within the viral cycle. Therefore, it is a therapeutic target for research of the new antiviral agents. Structure&ndash, activity relationships studies have revealed which are the important functional groups for the receptor&ndash, ligand interaction. Influenza virus type A NA activity was inhibited by five scaffolds without structural resemblance to sialic acid. Intending small organic compound repositioning along with drug repurposing, this study combined in silico simulations of ligand docking into the known binding site of NA, along with in vitro bioassays. The five proposed scaffolds are N-acetylphenylalanylmethionine, propanoic 3-[(2,5-dimethylphenyl) carbamoyl]-2-(piperazin-1-yl) acid, 3-(propylaminosulfonyl)-4-chlorobenzoic acid, ascorbic acid (vitamin C), and 4-(dipropylsulfamoyl) benzoic acid (probenecid). Their half maximal inhibitory concentration (IC50) was determined through fluorometry. An acidic reagent 2&prime, O-(4-methylumbelliferyl)-&alpha, dN-acetylneuraminic acid (MUNANA) was used as substrate for viruses of human influenza H1N1 or avian influenza H5N2. Inhibition was observed in millimolar ranges in a concentration-dependent manner. The IC50 values of the five proposed scaffolds ranged from 6.4 to 73 mM. The values reflect a significant affinity difference with respect to the reference drug zanamivir (p <, 0.001). Two compounds (N-acetyl dipeptide and 4-substituted benzoic acid) clearly showed competitive mechanisms, whereas ascorbic acid reflected non-competitive kinetics. The five small organic molecules constitute five different scaffolds with moderate NA affinities. They are proposed as lead compounds for developing new NA inhibitors which are not analogous to sialic acid.
- Published
- 2020
3. Identification of residues for chaperone-like activity of OppA protein in Yersinia pseudotuberculosis
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Lucia Soto Urzúa, Elena Escobar Garduño, Thomas Scior, and Luis Javier Martínez Morales
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0106 biological sciences ,lcsh:Biotechnology ,lcsh:QR1-502 ,Biophysics ,01 natural sciences ,Applied Microbiology and Biotechnology ,lcsh:Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,lcsh:TP248.13-248.65 ,010608 biotechnology ,Lactate dehydrogenase ,Yersinia pseudotuberculosis ,Analogy modeling ,Site-directed mutagenesis ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,Chemistry ,Periplasmic space ,biology.organism_classification ,OppA ,Enzyme ,Chaperone-like activity ,Biochemistry ,Membrane protein complex ,Chaperone (protein) ,biology.protein ,Original Article ,α-glucosidase ,Oligopeptide binding - Abstract
Periplasmic oligopeptide binding protein (OppA) is part of a multimeric cytoplasmic membrane protein complex, whose function is known as peptide transporters found in Gram-negative bacteria. A chaperone-like activity has been found for the OppA from Yersinia pseudotuberculosis, using biochemical experiments. Through computational analysis, we selected two amino acid residues (R41 and D42) that probably are involved in the chaperone-like activity. Our results to corroborate how OppA assists refolding and renaturation of lactate dehydrogenase and alpha-glucosidase denatured enzymes.
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- 2020
4. Binding of boswellic acids to functional proteins of the SARS‐CoV‐2 virus: Bioinformatic studies
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Hermann P. T. Ammon, Thomas Scior, and Reinhard H Caliebe
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education ,Pharmaceutical Science ,RNA-dependent RNA polymerase ,Antiviral Agents ,SARS‐CoV‐2 ,Structure-Activity Relationship ,Viral Proteins ,chemistry.chemical_compound ,Protein structure ,RNA polymerase ,Drug Discovery ,Humans ,boswellic acids ,Prodrugs ,Boswellia ,Polyproteins ,chemistry.chemical_classification ,Alanine ,Binding Sites ,Full Paper ,biology ,SARS-CoV-2 ,Anti-Inflammatory Agents, Non-Steroidal ,fungi ,COVID-19 ,Computational Biology ,Active site ,molecular docking ,Full Papers ,Adenosine Monophosphate ,Triterpenes ,COVID-19 Drug Treatment ,Nucleoprotein ,Amino acid ,Molecular Docking Simulation ,functional proteins ,Nucleoproteins ,chemistry ,Biochemistry ,RGS‐P3 ,Spike Glycoprotein, Coronavirus ,biology.protein ,Phosphorylation ,Glycoprotein ,Protein Binding - Abstract
Boswellic acids (BAs) have been shown to possess antiviral activity. Using bioinformatic methods, it was tested whether or not acetyl‐11‐keto‐β‐boswellic acid (AKBA), 11‐keto‐β‐boswellic acid (KBA), β‐boswellic acid (BBA), and the phosphorylated active metabolite of Remdesivir® (RGS‐P3) bind to functional proteins of SARS‐CoV‐2, that is, the replicase polyprotein P0DTD1, the spike glycoprotein P0DTC2, and the nucleoprotein P0DTC9. Using P0DTD1, AKBA and KBA showed micromolar binding affinity to the RNA‐dependent RNA polymerase (RdRp) and to the main proteinase complex Mpro. Phosphorylated BAs even bond in the nanomolar range. Due to their positive and negative charges, BAs and RGS‐P3 bond to corresponding negative and positive areas of the protein. BAs and RGS‐P3 docked in the tunnel‐like cavity of RdRp. BAs also docked into the elongated surface rim of viral Mpro. In both cases, binding occurred with active site amino acids in the lower micromolecular to upper nanomolar range. KBA, BBA, and RGS‐P3 also bond to P0DTC2 and P0DTC9. The binding energies for BAs were in the range of −5.8 to −6.3 kcal/mol. RGS‐P3 and BAs occluded the centrally located pore of the donut‐like protein structure of P0DTC9 and, in the case of P0DTC2, RGS‐P3 and BAs impacted the double‐wing‐like protein structure. The data of this bioinformatics study clearly show that BAs bind to three functional proteins of the SARS‐CoV‐2 virus responsible for adhesion and replication, as does RGS‐P3, a drug on the market to treat this disease. The binding effectiveness of BAs can be increased through phosphate esterification. Whether or not BAs are druggable against the SARS‐CoV‐2 disease remains to be established., Bioinformatic methods showed that acetyl‐11‐keto‐β‐boswellic acid, 11‐keto‐β‐boswellic acid, β‐boswellic acid, and the phosphorylated active metabolite of Remdesivir® bind to functional proteins of SARS‐CoV‐2: the replicase polyprotein P0DTD1, the spike glycoprotein P0DTC2, and the nucleoprotein P0DTC9. The binding effectiveness of the boswellic acids can be increased through phosphate esterification.
- Published
- 2021
5. Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum
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Raúl Argüello-García, Emanuel Hernández-Núñez, Ismael León-Rivera, Elizabeth Barbosa-Cabrera, Blanca Colín-Lozano, Manuel Jesús Chan-Bacab, Vanessa López-Guerrero, Rosa Moo-Puc, Benjamín Otto Ortega-Morales, Thomas Scior, and Gabriel Navarrete-Vázquez
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Giardiasis ,0301 basic medicine ,medicine.drug_class ,Antiparasitic ,Trypanosoma cruzi ,030106 microbiology ,Clinical Biochemistry ,Antiprotozoal Agents ,Pharmaceutical Science ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Leishmania mexicana ,Microbiology ,Mice ,03 medical and health sciences ,In vivo ,parasitic diseases ,Drug Discovery ,Trichomonas vaginalis ,medicine ,Animals ,Humans ,Molecular Biology ,Leishmania ,Protozoan Infections ,biology ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Organic Chemistry ,Nitazoxanide ,Nitro Compounds ,biology.organism_classification ,Thiazoles ,Metronidazole ,030104 developmental biology ,Drug Design ,Antiprotozoal ,Molecular Medicine ,Female ,Giardia lamblia ,medicine.drug - Abstract
We designed and synthesized five new 5-nitrothiazole-NSAID chimeras as analogues of nitazoxanide, using a DCC-activated amidation. Compounds 1-5 were tested in vitro against a panel of five protozoa: 2 amitochondriates (Giardia intestinalis, Trichomonas vaginalis) and 3 kinetoplastids (Leishmania mexicana, Leishmania amazonensis and Trypanosoma cruzi). All chimeras showed broad spectrum and potent antiprotozoal activities, with IC50 values ranging from the low micromolar to nanomolar order. Compounds 1-5 were even more active than metronidazole and nitazoxanide, two marketed first-line drugs against giardiasis. In particular, compound 4 (an indomethacin hybrid) was one of the most potent of the series, inhibiting G. intestinalis growth in vitro with an IC50 of 0.145μM. Compound 4 was 38-times more potent than metronidazole and 8-times more active than nitazoxanide. The in vivo giardicidal effect of 4 was evaluated in a CD-1 mouse model obtaining a median effective dose of 1.709μg/kg (3.53nmol/kg), a 321-fold and 1015-fold increase in effectiveness after intragastric administration over metronidazole and nitazoxanide, respectively. Compounds 1 and 3 (hybrids of ibuprofen and clofibric acid), showed potent giardicidal activities in the in vitro as well as in the in vivo assays after oral administration. Therefore, compounds 1-5 constitute promising drug candidates for further testing in experimental chemotherapy against giardiasis, trichomoniasis, leishmaniasis and even trypanosomiasis infections.
- Published
- 2017
6. Characterization of specific allosteric effects of the Na+ channel β1 subunit on the Nav1.4 isoform
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Lourdes Millan-PerezPeña, Bertin Paiz-Candia, Angel A. Islas, Thomas Scior, Alfredo Sánchez-Solano, and Eduardo M. Salinas-Stefanon
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0301 basic medicine ,Alanine ,Gene isoform ,Allosteric regulation ,Biophysics ,Membrane biology ,General Medicine ,Gating ,Biology ,Transmembrane protein ,03 medical and health sciences ,030104 developmental biology ,Biochemistry ,Extracellular ,Intracellular - Abstract
The mechanism of inactivation of mammalian voltage-gated Na+ channels involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the β1 subunit. Navβ1 subunits constitute single-pass transmembrane proteins that form protein–protein associations with pore-forming α subunits to allosterically modulate the Na+ influx into the cell during the action potential of every excitable cell in vertebrates. Here, we explored the role of the intracellular IFM motif of rNav1.4 (skeletal muscle isoform of the rat Na+ channel) on the α-β1 functional interaction and showed for the first time that the modulation of β1 is independent of the IFM motif. We found that: (1) Nav1.4 channels that lack the IFM inactivation particle can undergo a “C-type-like inactivation” albeit in an ultraslow gating mode; (2) β1 can significantly accelerate the inactivation of Nav1.4 channels in the absence of the IFM motif. Previously, we identified two residues (T109 and N110) on the β1 subunit that disrupt the α-β1 allosteric modulation. We further characterized the electrophysiological effects of the double alanine substitution of these residues demonstrating that it decelerates inactivation and recovery from inactivation, abolishes the modulation of steady-state inactivation and induces a current rundown upon repetitive stimulation, thus causing a general loss of function. Our results contribute to delineating the process of the mammalian Na+ channel inactivation. These findings may be relevant to the design of pharmacological strategies, targeting β subunits to treat pathologies associated to Na+ current dysfunction.
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- 2016
7. Substrate structure-activity relationship reveals a limited lipopolysaccharide chemotype range for intestinal alkaline phosphatase
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Timothy C. Meredith, Uwe Mamat, Thomas Scior, Dominik Schwudke, Nicolas Gisch, Ursula Schombel, Gloria Komazin, Ronald W. Woodard, and Michael Maybin
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0301 basic medicine ,Lipopolysaccharides ,Models, Molecular ,Lipopolysaccharide ,Phosphatase ,Biochemistry ,Microbiology ,Substrate Specificity ,Lipid A ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Escherichia coli ,Structure–activity relationship ,Animals ,Receptor ,Molecular Biology ,030102 biochemistry & molecular biology ,Molecular Structure ,Cell Biology ,Alkaline Phosphatase ,Intestines ,030104 developmental biology ,chemistry ,TLR4 ,Alkaline phosphatase ,lipids (amino acids, peptides, and proteins) ,Cattle ,Bacterial outer membrane - Abstract
Lipopolysaccharide (LPS) from the Gram-negative bacterial outer membrane potently activates the human innate immune system. LPS is recognized by the Toll-like receptor 4/myeloid differentiation factor-2 (TLR4/MD2) complex, leading to the release of pro-inflammatory cytokines. Alkaline phosphatase (AP) is currently being investigated as an anti-inflammatory agent for detoxifying LPS through dephosphorylating lipid A, thus providing a potential treatment for managing both acute (sepsis) and chronic (metabolic endotoxemia) pathologies wherein aberrant TLR4/MD2 activation has been implicated. Endogenous LPS preparations are chemically heterogeneous, and little is known regarding the LPS chemotype substrate range of AP. Here, we investigated the activity of AP on a panel of structurally defined LPS chemotypes isolated from Escherichia coli and demonstrate that calf intestinal AP (cIAP) has only minimal activity against unmodified enteric LPS chemotypes. P(i) was only released from a subset of LPS chemotypes harboring spontaneously labile phosphoethanolamine (PEtN) modifications connected through phosphoanhydride bonds. We demonstrate that the spontaneously hydrolyzed O-phosphorylethanolamine is the actual substrate for AP. We found that the 1- and 4′-lipid A phosphate groups critical in TLR4/MD2 signaling become susceptible to hydrolysis only after de-O-acylation of ester linked primary acyl chains on lipid A. Furthermore, PEtN modifications on lipid A specifically enhanced hTLR4 agonist activity of underacylated LPS preparations. Computational binding models are proposed to explain the limitation of AP substrate specificity imposed by the acylation state of lipid A, and the mechanism of PEtN in enhancing hTLR4/MD2 signaling.
- Published
- 2019
8. Why Antidiabetic Vanadium Complexes are Not in the Pipeline of 'Big Pharma' Drug Research? A Critical Review
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Philippe Bernard, Stefan Laufer, Thomas Scior, José Antonio Guevara-García, and Quoc-Tuan Do
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Drug Industry ,drug design ,Vanadium ,chemistry.chemical_element ,Pharmacology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Coordination Complexes ,Antidiabetics ,Drug Discovery ,Diabetes Mellitus ,Medicine ,Humans ,Hypoglycemic Agents ,Vanadium Compounds ,Drug industry ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,010405 organic chemistry ,business.industry ,insulinomimetics ,molecular modeling ,vanadium complexes ,Research ,Organic Chemistry ,PTP1B ,0104 chemical sciences ,Clinical Practice ,chemistry ,speciation ,Molecular Medicine ,Engineering ethics ,business ,Half-Life - Abstract
Public academic research sites, private institutions as well as small companies have made substantial contributions to the ongoing development of antidiabetic vanadium compounds. But why is this endeavor not echoed by the globally operating pharmaceutical companies, also known as "Big Pharma"? Intriguingly, today's clinical practice is in great need to improve or replace insulin treatment against Diabetes Mellitus (DM). Insulin is the mainstay therapeutically and economically. So, why do those companies develop potential antidiabetic drug candidates without vanadium (vanadium- free)? We gathered information about physicochemical and pharmacological properties of known vanadium-containing antidiabetic compounds from the specialized literature, and converted the data into explanations (arguments, the "pros and cons") about the underpinnings of antidiabetic vanadium. Some discoveries were embedded in chronological order while seminal reviews of the last decade about the Medicinal chemistry of vanadium and its history were also listed for further understanding. In particular, the concepts of so-called "noncomplexed or free" vanadium species (i.e. inorganic oxido-coordinated species) and "biogenic speciation" of antidiabetic vanadium complexes were found critical and subsequently documented in more details to answer the question.
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- 2016
9. Structure - Function Analysis of the Cytochromes P450, Responsible for Phenprocoumon Metabolism
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Israel Quiroga and Thomas Scior
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Phenprocoumon ,CYP3A4 ,Biochemistry ,Chemistry ,Docking (molecular) ,medicine ,General Chemistry ,CYP2C19 ,Metabolism ,CYP2C8 ,Molecular mechanics ,CYP2C9 ,medicine.drug - Abstract
Phenprocoumon is an oral anticoagulant used for the prophylaxis and treatment of disorders due to thrombosis. However, if oral anticoagulants are not metabolized, they could exacerbate and generate clotting disorders. Phenprocoumon is metabolized by at least four hepatic enzymes members of the cytochromes P450 family; three of which are members of the same subfamily (CYP2C9, CYP2C19 and CYP2C8). Even with too many differences in their amino acid sequence and tertiary structures, CYP2C9 and CYP3A4 have the most similar metabolic activity on phenprocoumon. In this study, we were able to explain these activity similarities using force fields of molecular mechanics for geometry and energy optimization in combination with docking techniques. The results were compared to study Structure-Function Relationships (SFR) of our four target proteins (CYP2C9, CYP2C19, CYP2C8 and CYP3A4). The study and prediction of metabolism and sites of metabolisms of drugs was successfully performed using this approach.
- Published
- 2018
10. Predicting a double mutant in the twilight zone of low homology modeling for the skeletal muscle voltage-gated sodium channel subunit beta-1 (Nav1.4 β1)
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Lourdes Millán-Pérez Peña, Eduardo M. Salinas-Stefanon, Thomas Scior, Alfredo Sánchez-Solano, Angel A. Islas, Claudia Mancilla-Simbro, and Bertin Paiz-Candia
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Protein subunit ,lcsh:Biotechnology ,Mutant ,Biophysics ,Trk, tyrosine receptor ,SDM, site-directed mutagenesis ,Bioinformatics ,Biochemistry ,Homology (biology) ,Article ,TLR4, Toll-like receptor type 4 ,Structural Biology ,lcsh:TP248.13-248.65 ,Genetics ,Analogy modeling ,Homology modeling ,Site-directed mutagenesis ,Protein secondary structure ,Alanine ,Chemistry ,Sodium channel ,Computer Science Applications ,MD-2 ,Ig-like ,MD-2, myeloid differentiation factor 2 (MD-2) ,CDR1 ,Nav1.4, skeletal muscle voltage-gated sodium channel ,Patch-clamp ,Biotechnology - Abstract
The molecular structure modeling of the β1 subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4) was carried out in the twilight zone of very low homology. Structural significance can per se be confounded with random sequence similarities. Hence, we combined (i) not automated computational modeling of weakly homologous 3D templates, some with interfaces to analogous structures to the pore-bearing Nav1.4 α subunit with (ii) site-directed mutagenesis (SDM), as well as (iii) electrophysiological experiments to study the structure and function of the β1 subunit. Despite the distant phylogenic relationships, we found a 3D-template to identify two adjacent amino acids leading to the long-awaited loss of function (inactivation) of Nav1.4 channels. This mutant type (T109A, N110A, herein called TANA) was expressed and tested on cells of hamster ovary (CHO). The present electrophysiological results showed that the double alanine substitution TANA disrupted channel inactivation as if the β1 subunit would not be in complex with the α subunit. Exhaustive and unbiased sampling of “all β proteins” (Ig-like, Ig) resulted in a plethora of 3D templates which were compared to the target secondary structure prediction. The location of TANA was made possible thanks to another “all β protein” structure in complex with an irreversible bound protein as well as a reversible protein–protein interface (our “Rosetta Stone” effect). This finding coincides with our electrophysiological data (disrupted β1-like voltage dependence) and it is safe to utter that the Nav1.4 α/β1 interface is likely to be of reversible nature.
- Published
- 2015
11. Interference of Boswellic Acids with the Ligand Binding Domain of the Glucocorticoid Receptor
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Thomas Scior, Itzel Gutierrez-Aztatzi, Moritz Verhoff, Stefan Laufer, Oliver Werz, and Hermann P. T. Ammon
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Luciferase reporter ,Chemistry ,General Chemical Engineering ,education ,Anti-Inflammatory Agents ,Antagonist ,Positive control ,General Chemistry ,Library and Information Sciences ,Ligand binding domain ,Ligands ,Dexamethasone ,Triterpenes ,Computer Science Applications ,Molecular Docking Simulation ,Structure-Activity Relationship ,Receptors, Glucocorticoid ,Glucocorticoid receptor ,Biochemistry ,Molecular mechanism ,Humans ,Pharmacophore ,Glucocorticoids ,hormones, hormone substitutes, and hormone antagonists ,Protein Binding - Abstract
Boswellic acids (BAs) possess anti-inflammatory properties in various biological models with similar features to those of glucocorticoids (GCs), such as suppression of the release of pro-inflammatory cytokines. Hence, the molecular mechanism of BAs responsible for their anti-inflammatory features might be attributable to interference with the human glucocorticoid receptor (GR). Due to obvious structural similarities with GCs, we conducted pharmacophore studies as well as molecular docking simulations of BAs as putative ligands at the ligand binding site (LBS) of the GR in distinct functional states. In order to verify receptor binding and functional activation of the GR by BAs, radiometric binding assays as well as GR response element-dependent luciferase reporter assay were performed with dexamethasone (DEX) as a functional positive control. With respect to the observed position of GCs in GR crystal complexes in the active antagonist state, BAs docked in a flipped orientation with estimated binding constants reflecting nanomolar affinities. For validation, DEX and other steroids were successfully redocked into their crystal poses in similar ranges as reported in the literature. In line with the pharmacophore and docking models, the BAs were strong GR binders (radiometric binding assay), albeit none of the BAs activated the GR in the reporter gene assay, when compared to the GC agonist DEX. The flipped scaffolds of all BAs dislodge the known C-11 function from its receiving amino acid (Asn564), which may explain the silencing effects of receptor-bound BAs in the reporter gene assay. Together, our results constitute a compelling example of rigid keys acting in an adaptable lock qualifying as a reversed induced fit mechanism, thereby extending the hitherto published knowledge about molecular target interactions of BAs.
- Published
- 2014
12. Pharmacophore Design of p38α MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted or 1,2,4,5-Tetrasubstituted Imidazole Scaffold
- Author
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Thomas Scior, Karina Cuanalo-Contreras, David M Domeyer, and Stefan Laufer
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Pharmacology ,Pyrimidine ,Stereochemistry ,Ligand ,Organic Chemistry ,Ring (chemistry) ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Pyridine ,Side chain ,Molecular Medicine ,Imidazole ,Pharmacophore ,Binding selectivity - Abstract
Synthetic compounds with a tri- and tetra-substituted imidazole scaffold are known as selective inhibitors of the p38 mitogen-activated protein (MAP) kinase responsible for proinflammatory cytokine release. The scope is to review the literature describing their design, synthesis and activity studies. To date a great plethora of crystal structures of p38 in complex with small organic ligands have been published. Cocrystallized ligand information is of particular interest to our review study, i.e. ATP itself, the reference inhibitor SB203580 with its aryl-pyridinyl-imidazoles and related imidazole and pyrimidine-based derivatives. The selective inhibitors bind to the pocket of adenosine 5'-triphoshate (ATP) replacing the latter. The hydrophobic region II, however, is not occupied by the natural binder ATP, but accommodates the pyridine substituents preserving the 4-fluorophenyl ring occupation in pocket I as a prerequisite to gain higher binding selectivity and potency than the reference compound SB203580 (4-[5-(4-fluoro-phenyl)-2-(4-methanesulfinyl-phenyl)-3himidazol-4-yl]-pyridine). Experimental and computed work is reviewed which evidence that the 2 position of the pyrimidine ring is amenable to the introduction of a side chain and the replacement of pyridine in SB203580 by a pyrimidine ring improves both inhibitory activity and selectivity for p38 over other kinases. All ligands with a pyridyl C2 side chain occupy the hydrophobic pocket II and in some cases a double hydrogen bond is reported between methionine 109 and glycine 110 of the hinge region, following an observed backbone shift. The substituted pyridine ring binds stronger than the two other side chains on the imidazole scaffold.
- Published
- 2011
13. How to Recognize and Workaround Pitfalls in QSAR Studies: A Critical Review
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J. A. Yunes Rojas, José L. Medina-Franco, Philippe Bernard, Karina Martinez-Mayorga, Thomas Scior, and Quoc-Tuan Do
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Models, Molecular ,Pharmacology ,Principal Component Analysis ,Quantitative structure–activity relationship ,Management science ,Computer science ,Workaround ,Organic Chemistry ,Quantitative Structure-Activity Relationship ,Biochemistry ,Cheminformatics ,Drug Discovery ,Regression Analysis ,Molecular Medicine ,Least-Squares Analysis ,Set (psychology) ,Algorithms - Abstract
Quantitative Structure-Activity Relationships (QSAR) are based on the hypothesis that changes in molecular structure reflect proportional changes in the observed response or biological activity. In order to successfully conduct QSAR studies certain conditions have to be met that are not frequently reported in the literature. This suggests that some authors are not aware of the principle flaws, occasional shortcomings, and circumstantial downsides of QSAR methods. The present paper focuses on prerequisites to set up correct models and on limitations of model applications. Their implications are systematically described and illustrated as pitfalls that have strong implications in QSAR, and possible solutions are suggested. The paper is focused on small scale 2D- and 3D-QSAR studies for lead optimization. The work is enriched with comprehensive comments and non-mathematical explanations for the computer practitioner in Medicinal Chemistry.
- Published
- 2009
14. Elucidating Isoniazid Resistance Using Molecular Modeling
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Yee Siew Choong, Thomas Scior, Habibah A. Wahab, Pazilah Ibrahim, and Amirin Sadikun
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Models, Molecular ,Informatics ,Protein Conformation ,General Chemical Engineering ,Mutant ,Drug resistance ,Library and Information Sciences ,Reductase ,Ligands ,Mycobacterium tuberculosis ,Bacterial Proteins ,Mutant protein ,Catalytic Domain ,Drug Resistance, Bacterial ,Isoniazid ,medicine ,biology ,INHA ,Wild type ,Water ,General Chemistry ,NAD ,biology.organism_classification ,Computer Science Applications ,Biochemistry ,Genes, Bacterial ,Mutation ,Thermodynamics ,Oxidoreductases ,medicine.drug - Abstract
The continuing rise in tuberculosis incidence and the problem of drug resistance strains have prompted the research on new drug candidates and the mechanism of drug resistance. Molecular docking and molecular dynamics simulation (MD) were performed to study the binding of isoniazid onto the active site of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) in an attempt to address the mycobacterial resistance against isoniazid. Results show that isonicotinic acyl-NADH (INADH) has an extremely high binding affinity toward the wild type InhA by forming stronger interactions compared to the parent drug (isoniazid) (INH). Due to the increase of hydrophobicity and reduction in the side chain's volume of A94 of mutant type InhA, both INADH and the mutated protein become more mobile. Due to this reason, the molecular interactions of INADH with mutant type are weaker than that observed with the wild type. However, the reduced interaction caused by the fluctuation of INADH and the mutant protein only inflected minor resistance in the mutant strain as inferred from free energy calculation. MD results also showed there exists a water-mediated hydrogen bond between INADH and InhA. However, the bridged water molecule is only present in the INADH-wild type complex, reflecting the putative role of the water molecule in the binding of INADH to the wild type protein. The results support the assumption that the conversion of prodrug isoniazid into its active form INADH is mediated by KatG as a necessary step prior to target binding on InhA. Our findings also contribute to a better understanding of INH resistance in mutant type.
- Published
- 2008
15. In silico analysis identifies a C3HC4-RING finger domain of a putative E3 ubiquitin-protein ligase located at the C-terminus of a polyglutamine-containing protein
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J.F. Sánchez-Ruiz, Wolfhard Koch, Thomas Scior, and F. Luna
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RING finger structure ,Physiology ,Immunology ,Biophysics ,Protein Data Bank (RCSB PDB) ,Ocean Engineering ,Sequence alignment ,Biochemistry ,E3 ubiquitin-protein ligase ,Low homology model ,Homology modeling ,General Pharmacology, Toxicology and Pharmaceutics ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,Zinc finger ,lcsh:R5-920 ,DNA ligase ,biology ,General Neuroscience ,Cell Biology ,General Medicine ,computer.file_format ,Protein Data Bank ,Ubiquitin ligase ,RING finger domain ,lcsh:Biology (General) ,chemistry ,biology.protein ,lcsh:Medicine (General) ,computer - Abstract
Almost identical polyglutamine-containing proteins with unknown structures have been found in human, mouse and rat genomes (GenBank AJ277365, AF525300, AY879229). We infer that an identical new gene (RING) finger domain of real interest is located in each C-terminal segment. A three-dimensional (3-D) model was generated by remote homology modeling and the functional implications are discussed. The model consists of 65 residues from terminal position 707 to 772 of the human protein with a total length of 796 residues. The 3-D model predicts a ubiquitin-protein ligase (E3) as a binding site for ubiquitin-conjugating enzyme (E2). Both enzymes are part of the ubiquitin pathway to label unwanted proteins for subsequent enzymatic degradation. The molecular contact specificities are suggested for both the substrate recognition and the residues at the possible E2-binding surface. The predicted structure, of a ubiquitin-protein ligase (E3, enzyme class number 6.3.2.19, CATH code 3.30.40.10.4) may contribute to explain the process of ubiquitination. The 3-D model supports the idea of a C3HC4-RING finger with a partially new pattern. The putative E2-binding site is formed by a shallow hydrophobic groove on the surface adjacent to the helix and one zinc finger (L722, C739, P740, P741, R744). Solvent-exposed hydrophobic amino acids lie around both zinc fingers (I717, L722, F738, or P765, L766, V767, V733, P734). The 3-D structure was deposited in the protein databank theoretical model repository (2B9G, RCSB Protein Data Bank, NJ).
- Published
- 2007
16. Homology Modelling of a Newly Discovered Thioredoxin Protein and Analysis of the Force Field and Electrostatic Properties
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Victoria I. Bunik, Hans Bisswanger, Günter Raddatz, and Thomas Scior
- Subjects
chemistry.chemical_classification ,Receptor complex ,biology ,Organic Chemistry ,Active site ,Ferredoxin-thioredoxin reductase ,Thioredoxin fold ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Ribonucleotide reductase ,Computational Theory and Mathematics ,Biochemistry ,chemistry ,Oxidoreductase ,biology.protein ,Physical and Theoretical Chemistry ,Thioredoxin ,Cysteine - Abstract
Thioredoxin is a small protein (Mr approximately 12,000) found in all living cells from archaebacteria to humans. The active site is highly conserved and has two redox-active cysteine residues in the sequence: -Trp-Cys-Gly-Pro-Cys-. Besides the function of the reduced form as a powerful protein disulfide oxidoreductase, thioredoxin is known to regulate and activate different target enzymes, i.e. ribonucleotide reductase and the mitochondrial 2-oxoacid dehydrogenase multienzyme complexes. Despite the high degree of homology between thioredoxin proteins from different species, there exists a strong variation in the capability of activating target enzymes. This is yet unexplainable, since there still exists no model of a thioredoxin/receptor complex.
- Published
- 1997
17. Three-dimensional mapping of differential amino acids of human, murine, canine and equine TLR4/MD-2 receptor complexes conferring endotoxic activation by lipid A, antagonism by Eritoran and species-dependent activities of Lipid IVA in the mammalian LPS sensor system
- Author
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Jorge Lozano-Aponte, Vianihuini Figueroa-Vazquez, Christian Alexander, Ulrich Zähringer, Julian A. Yunes-Rojas, and Thomas Scior
- Subjects
Molecular model ,Lipopolysaccharide ,lcsh:Biotechnology ,Biophysics ,Biology ,Biochemistry ,Lipid A ,chemistry.chemical_compound ,Structural Biology ,lcsh:TP248.13-248.65 ,Genetics ,Receptor ,Eritoran ,Research Articles ,chemistry.chemical_classification ,Ligand ,molecular modeling ,lipopolysaccharide ,Computer Science Applications ,Amino acid ,Toll-like receptors ,chemistry ,7 INGENIERÍA Y TECNOLOGÍA ,MD-2 ,Docking (molecular) ,docking ,Biotechnology - Abstract
A literature review concerning the unexpected species differences of the vertebrate innate immune response to lipid IVA was published in CSBJ prior to the present computational study to address the unpaired activity-sequence correlation of prototypic E. coli-type lipid A and its precursor lipid IVA regarding human, murine, equine and canine species. To this end, their sequences and structures of hitherto known Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 (MD-2) complexes were aligned and their differential side chain patterns studied. If required due to the lack of the corresponding X-ray crystallographic data, three-dimensional models of TLR4/MD-2/ligand complexes were generated using mono and dimeric crystal structures as templates and in silico docking of the prototypic ligands lipid A, lipid IVA and Eritoran. All differential amino acids were mapped to pinpoint species dependency on an atomic scale, i.e. the possible concert of mechanistically relevant side chains. In its most abstract and general form the three-dimensional (3D-) models devise a triangular interface or "wedge" where molecular interactions between TLR4, MD-2 and ligand itself take place. This study identifies two areas in the wedge related to either agonism or antagonism reflecting why ligands like lipid IVA can possess a species dependent dual activity. Lipid IVA represents an imperfect (underacylated and backbone-flipped), low affinity ligand of mammalian TLR4/MD-2 complexes. Its specific but weak antagonistic activity in the human system is in particular due to the loss of phosphate attraction in the wedge-shaped region conferred by nonhomologous residue changes when compared to crystal and modeled structures of the corresponding murine and equine TLR4/MD-2 complexes. The counter-TLR4/MD-2 unit was also taken into account since agonist-mediated dimerization in a defined m-shaped complex composed of two TLR4/MD-2/agonist subunits triggers intracellular signaling during the innate immune response to bacterial endotoxin exposure. © 2013 Scior et al.
- Published
- 2013
18. Reviewing and identifying amino acids of human, murine, canine and equine TLR4 / MD-2 receptor complexes conferring endotoxic innate immunity activation by LPS/lipid A, or antagonistic effects by Eritoran, in contrast to species-dependent modulation by lipid IVa
- Author
-
Thomas Scior, Ulrich Zaehringer, and Christian Alexander
- Subjects
Receptor complex ,Lipopolysaccharide ,lcsh:Biotechnology ,Mini Reviews ,Biophysics ,Biology ,Biochemistry ,Lipid A ,chemistry.chemical_compound ,Biosynthesis ,Structural Biology ,lcsh:TP248.13-248.65 ,Genetics ,Receptor ,Eritoran ,chemistry.chemical_classification ,lipopolysaccharide ,Computer Science Applications ,Amino acid ,Toll-like receptors ,chemistry ,MD-2 ,TLR4 ,lipids (amino acids, peptides, and proteins) ,sense organs ,Biotechnology - Abstract
There is literature evidence gathered throughout the last two decades reflecting unexpected species differences concerning the immune response to lipid IVa which provides the opportunity to gain more detailed insight by the molecular modeling approach described in this study. Lipid IVa is a tetra-acylated precursor of lipid A in the biosynthesis of lipopolysaccharide (LPS) in Gram-negative bacteria. Lipid A of the prototypic E. coli-type is a hexa-acylated structure that acts as an agonist in all tested mammalian species by innate immunorecognition via the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) receptor complex. In contrast, lipid IVa is proinflammatory in mouse cells (agonism) but it remains inactive to human macrophages and even antagonizes the action of potent agonists like E. coli-type lipid A. This particular ambivalent activity profile of lipid IVa has been confirmed in other mammalian species: in equine cells Lipid IVa also acts in a weak agonistic manner, whereas being inactive and antagonizing the lipid A-induced activation of canine TLR4/MD-2. Intriguingly, the respective TLR4 amino acid sequences of the latter species are more identical to the human (67%, 68%) than to the murine (62%, 58%) ortholog. In order to address the unpaired activity-sequence dualism for human, murine, canine and equine species regarding the activity of lipid IVa as compared to LPS and lipid A and, we review the literature and computationally pinpoint the differential biological effects of lipid IVa versus LPS and lipid A to specific amino acid residues. In contrast to lipid IVa the structurally related synthetic compound Eritoran (E5564) acts consistently in an antagonistic manner in these mammalian species and serves as a reference ligand for molecular modeling in this study. The combined evaluation of data sets provided by prior studies and in silico homology mapping of differential residues of TLR4/MD-2 complexes lends detailed insight into the driving forces of the characteristic binding modes of the lipid A domain in LPS and the precursor structure lipid IVa to the receptor complex in individual mammalian species.
- Published
- 2013
19. Adenosine receptors and their modulators
- Author
-
Thomas Scior and Christa E. Müller
- Subjects
Purine ,Agonist ,Base Sequence ,medicine.drug_class ,Molecular Sequence Data ,Purinergic receptor ,Receptors, Purinergic P1 ,Pharmacology ,Biology ,Xanthine ,Adenosine ,Adenosine receptor ,chemistry.chemical_compound ,Purinergic P1 Receptor Antagonists ,chemistry ,Biochemistry ,medicine ,Animals ,Humans ,Molecular Medicine ,Amino Acid Sequence ,General Pharmacology, Toxicology and Pharmaceutics ,Signal transduction ,Receptor ,medicine.drug - Abstract
The identification and characterization of adenosine receptors and the development of potent, receptor subtype-selective agonists and antagonists has been an active area of research for the past 20 years. Major recent advances in the field have been the cloning of several adenosine receptor subtypes of different species, including the discovery of a new subtype, designated A3, the discovery and development of new agonists and antagonists, particularly those with selectivity for the A2a adenosine receptor, the characterization of signal transduction pathways, and the development of agents which act indirectly on the adenosine receptor system. The present article focusses on aspects of pharmaceutical/medicinal chemistry related to adenosine receptors.
- Published
- 1993
20. Elucidation of the fragmentation pathways of different phosphatidylinositol phosphate species (PIPx) using IRMPD implemented on a FT-ICR MS
- Author
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Thomas Scior, Buko Lindner, and Nicole Zehethofer
- Subjects
Models, Molecular ,Chemistry ,Stereochemistry ,Analytical chemistry ,Mass spectrometry ,Ion cyclotron resonance spectrometry ,Tandem mass spectrometry ,Biochemistry ,Analytical Chemistry ,chemistry.chemical_compound ,Fragmentation (mass spectrometry) ,Phosphatidylinositol Phosphates ,Tandem Mass Spectrometry ,Inositol ,Computer Simulation ,Infrared multiphoton dissociation ,Phosphatidylinositol ,Ion cyclotron resonance - Abstract
This work reports on the fragmentation of phosphoinositides by tandem mass spectrometry (MS/MS) and MS³ experiments on a hybrid apex-Qe Fourier transform-ion cyclotron resonance mass spectrometer (FT-ICR MS) using internal infrared multiphoton dissociation (IRMPD). The fragmentation behavior of diacylphophatidylinositol triphosphate was intensively studied since an abundant loss of inositol biphosphate was observed. This loss was suggested to occur via phosphate migration along the inositol head group. Substantiation by MS³ experiments showed that this neutral loss is formed after the loss of water from the precursor ion, indicating phosphate migration along the inositol ring to the glycerol backbone. Further fragmentation of the ion formed by the loss of inositol biphosphate from diacylphophatidylinositol triphosphate resulted in the formation of a product ion with a molecular formula of C(3)H(5)O(7)P(2), corresponding to a glycerol backbone linked to two phosphate groups. We suggested different structures for this ion and compared their stability using modeling experiments.
- Published
- 2010
21. Structure-function analysis of two variants of mumps virus hemagglutinin-neuraminidase protein
- Author
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Thomas Scior, Julio Reyes-Leyva, Gerardo Santos-López, Irma Herrera-Camacho, Verónica Vallejo-Ruiz, José Tapia-Ramírez, and María del Tránsito Borraz-Argüello
- Subjects
Microbiology (medical) ,lcsh:QR1-502 ,Mumps Vaccine ,Sialic acid binding ,Mumps virus ,Biology ,Sialidase ,medicine.disease_cause ,lcsh:Microbiology ,lcsh:Infectious and parasitic diseases ,chemistry.chemical_compound ,Structure-Activity Relationship ,paramyxovirus ,Cell Line, Tumor ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Point Mutation ,3D structure prediction ,lcsh:RC109-216 ,HN Protein ,Vero Cells ,Point mutation ,Hemagglutinin-neuraminidasa ,Genetic Variation ,Sialic acid ,Infectious Diseases ,chemistry ,Biochemistry ,Amino Acid Substitution ,sialic acid ,mumps virus ,Hemagglutinin-neuraminidase ,Alpha helix - Abstract
A point mutation from guanine (G) to adenine (A) at nucleotide position 1081 in the hemagglutinin-neuraminidase (HN) gene has been associated with neurovirulence of Urabe AM9 mumps virus vaccine. This mutation corresponds to a glutamic acid (E) to lysine (K) change at position 335 in the HN glycoprotein. We have experimentally demonstrated that two variants of Urabe AM9 strain (HN-A1081 and HN-G1081) differ in neurotropism, sialic acidbinding affinity and neuraminidase activity. In the present study, we performed a structure-function analysis of that amino acid substitution; the structures of HN protein of both Urabe AM9 strain variants were predicted. Based on our analysis, the E/K mutation changes the protein surface properties and to a lesser extent their conformations, which in turn reflects in activity changes. Our modeling results suggest that this E/K interchange does not affect the structure of the sialic acid binding motif; however, the electrostatic surface differs drastically due to an exposed short alpha helix. Consequently, this mutation may affect the accessibility of HN to substrates and membrane receptors of the host cells. Our findings appear to explain the observed differences in neurotropism of these vaccine strains.
- Published
- 2009
22. Application of drug repositioning strategy to TOFISOPAM
- Author
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Thomas Scior, C. Dufresne-Favetta, C. Lugnier, Quoc-Tuan Do, S. Zubrzycki, F. Himbert, P. Favetta, Philippe Bernard, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Drug ,Models, Molecular ,media_common.quotation_subject ,Drug Evaluation, Preclinical ,Molecular Conformation ,Pharmacology ,Biochemistry ,Benzodiazepines ,Structure-Activity Relationship ,Phosphodiesterase-4 ,Drug Discovery ,medicine ,Computer Simulation ,PDE4 Inhibitors ,ComputingMilieux_MISCELLANEOUS ,Chromatography, High Pressure Liquid ,media_common ,Virtual screening ,Chemistry ,Organic Chemistry ,Tofisopam ,Stereoisomerism ,Reverse docking ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Drug repositioning ,Models, Chemical ,Molecular Medicine ,Phosphodiesterase 4 Inhibitors ,Biochemical mechanism ,medicine.drug - Abstract
Drug repositioning strategy is an interesting approach for pharmaceutical companies; especially to increase their productivity. SELNERGY(tm) is a reverse docking based-program able to virtually screen thousands of compounds on more than 2000 3D biological targets. This program was successfully applied to tofisopam and revealed that the isomers of tofisopam are able to fit with phosphodiesterase 4. This old drug was used as a racemic mixture to treat anxiety in the eighties and was recently shown to act as a PDE4 inhibitor. Thanks to this strategy we demonstrated that tofisopam acts via the inhibition of PDE4 in the submicromolar range. Moreover, we firstly showed that the S-enantiomer of tofisopam is ten times more active than R-enantiomer. The identification of the biochemical mechanism of tofisopam isomers now allows to reposition this drug in new therapeutic indications where modulation of cAMP via PDE4 inhibitors are possible.
- Published
- 2008
23. Synthesis, biological testing, and binding mode prediction of 6,9-diarylpurin-8-ones as p38 MAP kinase inhibitors
- Author
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Bernd Kammerer, Dominik Hauser, Thomas Scior, David M Domeyer, and Stefan Laufer
- Subjects
Binding Sites ,Molecular model ,Purinones ,Kinase ,Stereochemistry ,Chemistry ,Plasma protein binding ,AutoDock ,p38 Mitogen-Activated Protein Kinases ,Structure-Activity Relationship ,Adenosine Triphosphate ,Biochemistry ,Docking (molecular) ,Drug Design ,Drug Discovery ,Molecular Medicine ,Structure–activity relationship ,Thermodynamics ,Binding site ,Protein kinase A ,Hydrophobic and Hydrophilic Interactions ,Protein Binding - Abstract
Based on the purine scaffold of ATP, derivatives of 6,9-diarylpurine-8-one were prepared and tested for their ability to inhibit p38 MAP kinase, a key enzyme in the cellular regulation of proinflammatory cytokines. The inhibitor design combines the purine system of the authentic cosubstrate ATP with various phenyl moieties to explore the selectivity for the two hydrophobic regions of the kinase's ATP-binding cleft. The present study indicates a new binding mode of our scaffold to p38 MAP kinase, which comprises the desired structural features of ATP and the N-phenyl-N-purin-6-yl ureas previously published by Wan et al. Combinations of Autodock and FlexX docking with different scoring functions were used to assess the postulated binding mode. The predictive power of different docking-scoring combinations was determined. The presented results may form a solid basis for further optimization cycles since our theoretical findings are consistent with our experimental binding data and supported by the literature.
- Published
- 2007
24. Isoniazid is not a lead compound for its pyridyl ring derivatives, isonicotinoyl amides, hydrazides, and hydrazones: a critical review
- Author
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S J Garcés-Eisele and Thomas Scior
- Subjects
Cell Membrane Permeability ,Drug Industry ,Stereochemistry ,medicine.drug_class ,Antitubercular Agents ,Hydrazone ,Quantitative Structure-Activity Relationship ,Carboxamide ,Antimycobacterial ,Isonicotinic acid ,Hydrazide ,Biochemistry ,chemistry.chemical_compound ,Drug Stability ,Drug Discovery ,medicine ,Isoniazid ,Antibacterial agent ,Benzoic acid ,Pharmacology ,chemistry.chemical_classification ,Hydrolysis ,Organic Chemistry ,bacterial infections and mycoses ,Amides ,Enzymes ,chemistry ,Drug Design ,Molecular Medicine ,Lead compound - Abstract
The relationships between structure, disintegration and antituberculotic in vitro activity were studied for over 200 derivatives of isonicotinic acid hydrazide (isoniazid, INH). Conclusive evidence reflects that many compounds do not withstand the in vitro conditions. A pH dependant partial hydrolysis to INH occurs in the case of hydrazones, in analogy to well-known benzoic acid esters. Hydrazides and amides are cleaved into isonicotinic acid. In general, antimycobacterial potencies drop against INH except for two outliers probably with additional unspecific toxicity of their residues. Analyzing the complexity and heterogeneity of molecular events, trends linked to hydrolysis are found when structural features are clustered. Hammett sigma constants correlate to pK(a) values possessing a twofold descriptive meaning: (i) the cardinal increase of partial positive charge of the reaction center towards nucleophilic water attack and (ii) the ionization crucial for mycobacterial cell permeation through porins or lipid barriers. We review the literature concluding that many so-called "novel leads" are nothing else than precursors of an INH-based scaffold. In addition, INH ring-substitution or analogous backbones never achieve the efficiency of INH, itself a prodrug, which accumulates in Mycobacterium tuberculosis in form of its intrabacterial active principle(s) to which it is an optimal transport vehicle, evidencing that INH is not a promising lead compound at all.
- Published
- 2006
25. Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors
- Author
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Wolfgang Albrecht, Thomas Scior, David M Domeyer, Dominik Hauser, and Stefan Laufer
- Subjects
Purine ,Models, Molecular ,Binding Sites ,biology ,Kinase ,Stereochemistry ,Binding, Competitive ,p38 Mitogen-Activated Protein Kinases ,Cofactor ,Biological Testing ,Atp competitive ,chemistry.chemical_compound ,Structure-Activity Relationship ,Adenosine Triphosphate ,Biochemistry ,chemistry ,Cyclin-dependent kinase ,Purines ,Drug Discovery ,biology.protein ,Molecular Medicine ,Purine derivative ,Binding site ,Protein Kinase Inhibitors ,Protein Kinases - Abstract
On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
- Published
- 2005
26. Antitubercular isoniazid and drug resistance of Mycobacterium tuberculosis--a review
- Author
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Stefan Laufer, Thomas Scior, Iván Meneses Morales, Solón Javier Garcés Eisele, and David M Domeyer
- Subjects
Tuberculosis ,Isoniazid ,Pharmaceutical Science ,Drug resistance ,Mycobacterium tuberculosis ,Biology ,Prodrug ,Isonicotinic acid ,medicine.disease ,biology.organism_classification ,chemistry.chemical_compound ,Biochemistry ,chemistry ,Mechanism of action ,Bacterial Proteins ,Peroxidases ,Drug Discovery ,Tuberculosis, Multidrug-Resistant ,medicine ,Humans ,medicine.symptom ,medicine.drug ,Antibacterial agent - Abstract
Isoniazid is one of the most potent drugs available for tuberculosis treatment. As a pro-drug it requires activation, which is performed by catalase/peroxidase. The active principle, whose identity has not yet been determined unambiguously, then acts on at least one target molecule, the enoyl-acyl carrier protein, required for the synthesis of the vital mycolic acids present in the cell wall of the bacterium. Some other targets have been proposed in order to explain the unusual potency of isoniazid; however, the supporting data are still controversial. We thoroughly discuss the action of isoniazid, resistance mechanisms, and the possible active product, which includes an isonicotinic acid-NADH adduct as well as a meta-isomer of NADH. Both structures have been probed positively in a 3D modeling analysis.
- Published
- 2003
27. Ethnopharmacology and bioinformatic combination for leads discovery: application to phospholipase A(2) inhibitors
- Author
-
Marcel Hibert, Jean-Yves Berthon, Philippe Bernard, Thomas Scior, and Bruno Didier
- Subjects
Models, Molecular ,Molecular model ,Phospholipase A2 inhibitor ,Plant Science ,Horticulture ,Biology ,Biochemistry ,Phospholipases A ,chemistry.chemical_compound ,Phospholipase A2 ,Species Specificity ,Betulinic acid ,Enzyme Inhibitors ,Molecular Biology ,Chromatography, High Pressure Liquid ,chemistry.chemical_classification ,Phospholipase A ,Betulin ,Molecular Structure ,Plant Extracts ,Computational Biology ,General Medicine ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Design ,Ethnopharmacology ,biology.protein - Abstract
A program combining ethnopharmacology and bioinformatic approaches has successfully been applied on anti-inflammatory activity. (i) An ethnobotanical study allowed the identification of several plants associated with putative anti-inflammatory properties as potential leads. (ii) On the other hand, it is well known that phospholipase A(2) is a target implicated in the pro-inflammatory process. Thus, (iii) some selected plant extracts were experimentally tested on phospholipase A(2). Finally, (iv) these experimental results combined with bioinformatic tools, such as database exploitation and molecular modeling, allowed to suggest that one compound, betulin and its oxidative form betulinic acid, might be responsible of the anti-PLA(2) activity. This suggestion was confirmed experimentally.
- Published
- 2001
28. Prolyl isomerases in a minimal cell. Catalysis of protein folding by trigger factor from Mycoplasma genitalium
- Author
-
Thomas Scior, Andreas Pahl, Kay Brune, Anja Pecht, Werner Solbach, Holger Bang, and Guenter Raddatz
- Subjects
Models, Molecular ,Protein Folding ,Protein Conformation ,Recombinant Fusion Proteins ,Molecular Sequence Data ,Isomerase ,Biochemistry ,Catalysis ,Tacrolimus ,Substrate Specificity ,Tacrolimus Binding Proteins ,Protein structure ,Mycoplasma ,Bacterial Proteins ,Prolyl isomerase ,Escherichia coli ,Humans ,Amino Acid Sequence ,Cloning, Molecular ,Immunophilins ,Peptide sequence ,biology ,Sequence Homology, Amino Acid ,GroES ,Peptidylprolyl Isomerase ,GroEL ,Protein Structure, Tertiary ,Genes, Bacterial ,Chaperone (protein) ,biology.protein ,Protein folding ,Sequence Alignment ,Molecular Chaperones - Abstract
Peptidyl-prolyl cis/trans isomerases (PPIases) catalyze the isomerization of prolyl peptide bonds. Distinct families of this class of enzymes are involved in protein folding in vitro, whereas their significance in free living organisms is not known. Previously, we inspected the smallest known genome of a self-replicating organism and found that Mycoplasma genitalium is devoid of all known PPIases except the trigger factor. Despite the extensive sequence information becoming available, most genes remain hypothetical and enzyme activities in many species have not been assigned to an open reading frame. Therefore, we studied the PPIase activity in crude extracts of M. genitalium. We showed that this is solely attributed to a single enzyme activity, the trigger factor. Characterization of this enzyme revealed that its PPIase activity resides in a central 12-kDa domain. Only the complete trigger factor is able to cis/trans isomerize extended peptide substrates, while the PPIase domain alone can not. The N- and the C-terminal domains of the trigger factor seem to function in binding of proteins as substrates, as demonstrated by protein refolding experiments, in which the complete trigger factor catalyzed protein refolding towards a model protein 500-fold more efficiently than the isolated central PPIase domain. Protein modeling studies suggest that the PPIase domain can fold in a similar way as the PPIase domain of FK506 binding proteins (FKBPs), one class of PPIases, despite only very limited sequence homology. Differences at the active site explain why this enzyme is not inhibited by FK506 in contrast with FKBPs. Trigger factor expressed in Escherichia coli confirms its additional chaperone functions, as shown by its association with chaperones GroEL and GroES after induction of misfolding. In contrast, the isolated PPIase-domain lacks any association with chaperones from E. coli. In summary, trigger factor of M. genitalium is the single folding isomerase of this organism, which harbors an enzymatically active PPIase domain with structural homology to FKBPs. Its additional domains confer its ability to be an efficient catalyst of protein folding. The protein folding machinery is conserved and shows a dual function as a chaperone and a prolyl isomerase.
- Published
- 2000
29. Antidiabetic Bis-Maltolato-OxoVanadium(IV): Conversion of inactive trans- to bioactive cis-BMOV for possible binding to target PTP-1B
- Author
-
Thomas Scior, Hans-Georg Mack, Wolfhard Koch, and José Antonio Guevara García
- Subjects
Pharmacology ,Steric effects ,computational quantum chemistry ,Drug Design, Development and Therapy ,Aqueous solution ,Molecular model ,molecular modeling ,PTP-1B ,Stereochemistry ,Chemistry ,lcsh:RM1-950 ,Ab initio ,Pharmaceutical Science ,Prodrug ,Dosage form ,Cytosol ,lcsh:Therapeutics. Pharmacology ,Biochemistry ,vanadium compounds ,diabetes mellitus ,Drug Discovery ,Tyrosine ,Original Research - Abstract
Thomas Scior1, Hans-Georg Mack2, José Antonio Guevara García3, Wolfhard Koch41Departamento de Farmacia. Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Colonia San Manuel, Puebla, Mexico; 2Institut für Physikalische Chemie, Universität Tübingen, Tübingen, Germany; 3Laboratorio de Investigación en Bioinorgánica y Biorremediación (LIByB). Departamento de Ciencias Básicas, Ingeniería y Tecnología, Universidad Autónoma de Tlaxcala, Apizaco, Tlaxcala, Mexico; 4Facultad de Estudios Superiores Zaragoza (FESZ), Universidad Nacional Autónoma de México (UNAM), Colonia Ejército de Oriente, Delegación Iztapalapa, Mexico City, MexicoAbstract: The postulated transition of Bis-Maltolato-OxoVanadium(IV) (BMOV) from its inactive trans- into its cis-aquo-BMOV isomeric form in solution was simulated by means of computational molecular modeling. The rotational barrier was calculated with DFT – B3LYP under a stepwise optimization protocol with STO-3G, 3-21G, 3-21G*, and 6-31G ab initio basis sets. Our computed results are consistent with reports on the putative molecular mechanism of BMOV triggering the insulin-like cellular response (insulin mimetic) as a potent inhibitor of the protein tyrosine phosphatase-1B (PTP-1B). Initially, trans-BMOV is present in its solid dosage form but in aqueous solution, and during oral administration, it is readily converted into a mixture of “open-type” and “closed-type” complexes of cis-aquo-BMOV under equilibrium conditions. However, in the same measure as the “closed-type” complex binds to the cytosolic PTP-1B, it disappears from solution, and the equilibrium shifts towards the “closed-type” species. In full accordance, the computed binding mode of cis-BMOV is energetically favored over sterically hindered trans-BMOV. In view of our earlier report on prodrug hypothesis of vanadium organic compounds the present results suggest that cis-BMOV is the bioactive species.Keywords: vanadium compounds, diabetes mellitus, molecular modeling, computational quantum chemistry, PTP-1B
- Published
- 2008
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