The Experts below are selected from a list of 3828 Experts worldwide ranked by ideXlab platform
Michail S Kukharsky - One of the best experts on this subject based on the ideXlab platform.
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a Bioisostere of dimebon latrepirdine delays the onset and slows the progression of pathology in fus transgenic mice
CNS Neuroscience & Therapeutics, 2021Co-Authors: Kirill D Chaprov, Alexander P Rezvykh, Sergei Yu Funikov, T A Ivanova, Ekaterina A Lysikova, Alexei V Deykin, Michail S KukharskyAbstract:Aims To assess effects of DF402, a Bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein. Methods Mice received DF402 from the age of 42 days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre-symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA-seq was used to compare the spinal cord transcriptomes of wild-type, untreated, and DF402-treated FUS transgenic mice. Results DF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre-symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern. Conclusion DF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other Bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy.
Darren R. Dillard - One of the best experts on this subject based on the ideXlab platform.
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Rational design of small-molecule inhibitors for β-catenin/T-cell factor protein-protein interactions by Bioisostere replacement.
ACS chemical biology, 2013Co-Authors: Zheng Huang, Min Zhang, Darren R. DillardAbstract:A new hot spot-based design strategy using Bioisostere replacement is reported to rationally design nonpeptidic small-molecule inhibitors for protein–protein interactions. This method is applied to design new potent inhibitors for β-catenin/T-cell factor (Tcf) interactions. Three hot spot regions of Tcf for binding to β-catenin were quantitatively evaluated; the key binding elements around K435 and K508 of β-catenin were derived; a Bioisostere library was used to generate new fragments that can match the proposed critical binding elements. The most potent inhibitor, with a molecular weight of 230, has a Kd of 0.531 μM for binding to β-catenin and a Ki of 3.14 μM to completely disrupt β-catenin/Tcf interactions. The binding mode of the designed inhibitors was validated by the site-directed mutagenesis and structure–activity relationship (SAR) studies. This study provides a new approach to design new small-molecule inhibitors that bind to β-catenin and effectively disrupt β-catenin/Tcf interactions specific...
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rational design of small molecule inhibitors for β catenin t cell factor protein protein interactions by Bioisostere replacement
ACS Chemical Biology, 2013Co-Authors: Zheng Huang, Min Zhang, Darren R. DillardAbstract:A new hot spot-based design strategy using Bioisostere replacement is reported to rationally design nonpeptidic small-molecule inhibitors for protein–protein interactions. This method is applied to design new potent inhibitors for β-catenin/T-cell factor (Tcf) interactions. Three hot spot regions of Tcf for binding to β-catenin were quantitatively evaluated; the key binding elements around K435 and K508 of β-catenin were derived; a Bioisostere library was used to generate new fragments that can match the proposed critical binding elements. The most potent inhibitor, with a molecular weight of 230, has a Kd of 0.531 μM for binding to β-catenin and a Ki of 3.14 μM to completely disrupt β-catenin/Tcf interactions. The binding mode of the designed inhibitors was validated by the site-directed mutagenesis and structure–activity relationship (SAR) studies. This study provides a new approach to design new small-molecule inhibitors that bind to β-catenin and effectively disrupt β-catenin/Tcf interactions specific...
Peter Gmeiner - One of the best experts on this subject based on the ideXlab platform.
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structure based evolution of subtype selective neurotensin receptor ligands
ChemistryOpen, 2014Co-Authors: Carolin Schaab, Harald Hübner, Jurgen Einsiedel, Ralf C Kling, Timothy Clark, Dieter Seebach, Peter GmeinerAbstract:Subtype-selective agonists of the neurotensin receptor NTS2 represent a promising option for the treatment of neuropathic pain, as NTS2 is involved in the mediation of μ-opioid-independent anti-nociceptive effects. Based on the crystal structure of the subtype NTS1 and previous structure–activity relationships (SARs) indicating a potential role for the sub-pocket around Tyr11 of NT(8–13) in subtype-specific ligand recognition, we have developed new NTS2-selective ligands. Starting from NT(8–13), we replaced the tyrosine unit by β2-amino acids (type 1), by heterocyclic tyrosine Bioisosteres (type 2) and peptoid analogues (type 3). We were able to evolve an asymmetric synthesis of a 5-substituted azaindolylalanine and its application as a Bioisostere of tyrosine capable of enhancing NTS2 selectivity. The S-configured test compound 2 a, [(S)-3-(pyrazolo[1,5-a]pyridine-5-yl)-propionyl11]NT(8–13), exhibits substantial NTS2 affinity (4.8 nm) and has a nearly 30-fold NTS2 selectivity over NTS1. The (R)-epimer 2 b showed lower NTS2 affinity but more than 600-fold selectivity over NTS1.
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Phenyloxazoles and phenylthiazoles as benzamide Bioisosteres: synthesis and dopamine receptor binding profiles ☆
Bioorganic & medicinal chemistry letters, 2000Co-Authors: Jurgen Einsiedel, Harald Hübner, Christoph Thomas, Peter GmeinerAbstract:Conformationally restricted benzamide Bioisosteres were investigated when the aminomethylpyrrolidine derivative 4o proved D3 as well as D4 binding properties which were comparable to those of the atypical neuroleptics sulpiride and clozapine, respectively.
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Conjugated Enynes as Nonaromatic Catechol Bioisosteres: Synthesis, Binding Experiments, and Computational Studies of Novel Dopamine Receptor Agonists Recognizing Preferentially the D3 Subtype
Journal of medicinal chemistry, 2000Co-Authors: Harald Hübner, Christian Haubmann, Wolfgang Utz, Peter GmeinerAbstract:To evaluate nonaromatic catechol Bioisosteres, the conformationally restrained enynes 1 and enediynes 2 were synthesized via palladium-catalyzed coupling as the key reaction step. Subsequent recept...
Krishna A. Poojari - One of the best experts on this subject based on the ideXlab platform.
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Design and synthesis of low molecular weight compounds with complement inhibition activity.
Bioorganic & Medicinal Chemistry, 2005Co-Authors: H. E. Master, Shabana I. Khan, Krishna A. PoojariAbstract:An attempt was made to synthesize a series of non-cytotoxic low molecular weight compounds of varying substitutions and functionalities having pharmacophore activity like carbonyl compounds, carboxylic acid and Bioisosteres like tetrazole and phenyl acrylic acid. The in vitro assay of these analogues for the inhibition of complement activity revealed significant inhibitory activity for varying substituents and, particularly, for Bioisosteres, that is, tetrazole and phenyl acrylic acid derivatives.
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Synthesis of low molecular weight compounds with complement inhibition activity.
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: H. E. Master, Shabana I. Khan, Krishna A. PoojariAbstract:An attempt was made to synthesize a series of non-cytotoxic low molecular weight meta-substituted aromatic ethers (2-4, 5-7) and some of their Bioisosteres (14-16) and to evaluate their activity on the activation of human complement (classical pathway) and their intrinsic hemolytic activity. The in vitro assay results of the inhibition of complement-mediated hemolysis by these analogues indicate that the aldehydic meta substituted aromatic ethers show inhibitory potency, while carboxylic acid meta substituted aromatic ethers show hemolytic activity. Some of the Bioisosteres exhibit both inhibitory as well as hemolytic property.
Zheng Huang - One of the best experts on this subject based on the ideXlab platform.
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Rational design of small-molecule inhibitors for β-catenin/T-cell factor protein-protein interactions by Bioisostere replacement.
ACS chemical biology, 2013Co-Authors: Zheng Huang, Min Zhang, Darren R. DillardAbstract:A new hot spot-based design strategy using Bioisostere replacement is reported to rationally design nonpeptidic small-molecule inhibitors for protein–protein interactions. This method is applied to design new potent inhibitors for β-catenin/T-cell factor (Tcf) interactions. Three hot spot regions of Tcf for binding to β-catenin were quantitatively evaluated; the key binding elements around K435 and K508 of β-catenin were derived; a Bioisostere library was used to generate new fragments that can match the proposed critical binding elements. The most potent inhibitor, with a molecular weight of 230, has a Kd of 0.531 μM for binding to β-catenin and a Ki of 3.14 μM to completely disrupt β-catenin/Tcf interactions. The binding mode of the designed inhibitors was validated by the site-directed mutagenesis and structure–activity relationship (SAR) studies. This study provides a new approach to design new small-molecule inhibitors that bind to β-catenin and effectively disrupt β-catenin/Tcf interactions specific...
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rational design of small molecule inhibitors for β catenin t cell factor protein protein interactions by Bioisostere replacement
ACS Chemical Biology, 2013Co-Authors: Zheng Huang, Min Zhang, Darren R. DillardAbstract:A new hot spot-based design strategy using Bioisostere replacement is reported to rationally design nonpeptidic small-molecule inhibitors for protein–protein interactions. This method is applied to design new potent inhibitors for β-catenin/T-cell factor (Tcf) interactions. Three hot spot regions of Tcf for binding to β-catenin were quantitatively evaluated; the key binding elements around K435 and K508 of β-catenin were derived; a Bioisostere library was used to generate new fragments that can match the proposed critical binding elements. The most potent inhibitor, with a molecular weight of 230, has a Kd of 0.531 μM for binding to β-catenin and a Ki of 3.14 μM to completely disrupt β-catenin/Tcf interactions. The binding mode of the designed inhibitors was validated by the site-directed mutagenesis and structure–activity relationship (SAR) studies. This study provides a new approach to design new small-molecule inhibitors that bind to β-catenin and effectively disrupt β-catenin/Tcf interactions specific...