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71.
Weak Intermolecular Hydrogen Bonds with Fluorine: Detection and Implications for Enzymatic/Chemical Reactions,Chemical Properties,and Ligand/Protein Fluorine NMR Screening
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Dr. Claudio Dalvit Dr. Anna Vulpetti 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(22):7592-7601
It is known that strong hydrogen‐bonding interactions play an important role in many chemical and biological systems. However, weak or very weak hydrogen bonds, which are often difficult to detect and characterize, may also be relevant in many recognition and reaction processes. Fluorine serving as a hydrogen‐bond acceptor has been the subject of many controversial discussions and there are different opinions about it. It now appears that there is compelling experimental evidence for the involvement of fluorine in weak intramolecular or intermolecular hydrogen bonds. Using established NMR methods, we have previously characterized and measured the strengths of intermolecular hydrogen‐bond complexes involving the fluorine moieties CH2F, CHF2, and CF3, and have compared them with the well‐known hydrogen‐bond complex formed between acetophenone and the strong hydrogen‐bond donor p‐fluorophenol. We now report evidence for the formation of hydrogen bonds involving fluorine with significantly weaker donors, namely 5‐fluoroindole and water. A simple NMR method is proposed for the simultaneous measurement of the strengths of hydrogen bonds between an acceptor and a donor or water. Important implications of these results for enzymatic/chemical reactions involving fluorine, for chemical and physical properties, and for ligand/protein 19F NMR screening are analyzed through experiments and theoretical simulations. 相似文献
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Glutamine: fructose-6-phosphate amidotransferase (GFAT), also termed GFPT1 and GFAT1, catalyzes the first committed step of the hexosamine biosynthesis pathway in mammals and consequently plays an important role in type 2 diabetes. In the present study, a combination of pharmacophore modelling, homology modelling, and molecular docking analysis was performed to design new glutamine competitive inhibitors of human GFAT, and to investigate important interaction details of inhibitor molecules. A pharmacophore model of GFAT inhibitors was developed, subsequently validated, and utilized for the screening by the PHASE database to identify new molecules. Afterwards, homology modelling was performed to construct the glutamine-binding site of the GFAT protein. The modelled active site was utilized to dock the studied molecules to investigate important receptor-ligand interactions and to scrutinize database-screened molecules on the basis of essential interactions. This systematic in silico protocol helped us to identify new molecules that would be explored for the treatment of type 2 diabetes and its complications. 相似文献
74.
Identification of Compounds that Selectively Stabilize Specific G‐Quadruplex Structures by Using a Thioflavin T‐Displacement Assay as a Tool
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Dr. Jan Jamroskovic Dr. Madeleine Livendahl Dr. Jonas Eriksson Dr. Erik Chorell Dr. Nasim Sabouri 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(52):18932-18943
Small molecules are used in the G‐quadruplex (G4) research field in vivo and in vitro, and there are increasing demands for ligands that selectively stabilize different G4 structures. Thioflavin T (ThT) emits an enhanced fluorescence signal when binding to G4 structures. Herein, we show that ThT can be competitively displaced by the binding of small molecules to G4 structures and develop a ThT‐displacement high‐throughput screening assay to find novel and selective G4‐binding compounds. We screened approximately 28 000 compounds by using three different G4 structures and identified eight novel G4 binders. Analysis of the structural conformation and stability of the G4 structures in presence of these compounds demonstrated that the four compounds enhance the thermal stabilization of the structures without affecting their structural conformation. In addition, all four compounds also increased the G4‐structure block of DNA synthesis by Taq DNA polymerase. Also, two of these compounds showed selectivity between certain Schizosaccharomyces pombe G4 structures, thus suggesting that these compounds or their analogues can be used as selective tools for G4 DNA studies. 相似文献
75.
《中国化学会会志》2017,64(7):822-832
New water‐soluble pyridinium amines ( 2–8 ) were obtained by the solid‐state reactions of 4‐chloro‐1‐methylpyridin‐1‐ium triflate ( 1 ) and various primary aromatic amines. These compounds were characterized by 1H , 13C NMR , FTIR , UV –vis, and fluorescence spectroscopic methods along with single‐crystal X‐ray structure determination. The interaction potentials of all newly synthesized compounds with calf thymus DNA (CT‐DNA ) were investigated by UV –vis and florescence spectroscopy accompanied by docking studies. UV –vis spectroscopy indicated that the binding of compounds with CT‐DNA takes place via the intercalative mode. The compounds were also screened for their potential as antioxidants and enzyme inhibition agents. Some compounds displayed excellent butyrylcholine and acetylcholine esterase inhibition activities and were effective in scavenging the 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH ) radical in a dose‐dependent manner comparable to a standard. 相似文献
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A. Jarrahpour M. Motamedifar M. Zarei M. H. Youssoufi M. Mimouni Z. H. Chohan 《Phosphorus, sulfur, and silicon and the related elements》2013,188(2):491-497
We report in this article the design and calculated molecular properties of 18 new mono-cyclic β-lactams 4–21, on the basis of one hypothetical antibacterial pharmacophore structure designed to interact with both of Gram-positive bacteria and Gram-negative bacteria. The in vitro biological evaluation of these compounds allowed us to point out new potential non-nucleoside hits, with MIC values in the range of 2–8 μg/mL active against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. A correlation structure/antibacterial activities relationship of these monocyclic β-lactams is described. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. 相似文献
78.
N‐vinylimidazole (VIM), and phenacyl methacrylate (PAMA) copolymerized with different feed ratios using 1,4‐dioxane as a solvent and α,α'‐azobisisobutyronitrile (AIBN) as an initiator at 60°C. Structure and composition of copolymers for a wide range of monomer feed were determined by elemental analysis (content of N for VIM‐units) and by Fourier transform infrared spectroscopy through recorded analytical absorption bands for VIM (670 cm?1 for C‐N of imidazole ring) and PAMA (1730 cm?1 for C?O of ester group) units, respectively. Monomer reactivity ratios for VIM (M1)‐PAMA (M2) pair were determined by the application of conventional linearization methods such as Fineman‐Ross (F‐R) and Kelen‐Tüdös (KT) and a nonlinear error invariable model method using a computer program RREVM. The molecular weights (w and n) and polydispersity indices of the polymers were determined using gel permeation chromatography (GPC). Thermal behaviors of copolymers with various compositions were investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Also, the apparent thermal decomposition activation energies (ΔEd) were calculated by Ozawa method using the SETARAM Labsys TGA thermobalance. The antibacterial and antifungal effects of polymers were also tested on various bacteria, fungi and yeast. 相似文献
79.
HIV-1 integrase (IN) is a retroviral enzyme that catalyses integration of the reverse-transcribed viral DNA into the host genome, which is necessary for efficient viral replication. In this study, we have performed an in silico virtual screening for the identification of potential HIV-1 IN strand transfer (ST) inhibitors. Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to 3-Hydroxypyrimidine-2,4-diones. Based on the ligand-based pharmacophore model, we obtained a five-point pharmacophore with two hydrogen bond acceptors (A), one hydrogen bond donor (D), one hydrophobic group (H) and one aromatic ring (R) as pharmacophoric features. The pharmacophore hypothesis AADHR was used as a 3D query in a sequential virtual screening study to filter small molecule databases Maybridge, ChemBridge and Asinex. Hits matching with pharmacophore hypothesis AADHR were retrieved and passed progressively through Lipinski’s rule of five filtering, molecular docking and hierarchical clustering. The five compounds with best hits with novel and diverse chemotypes were subjected to QM/MM docking, which showed improved docking accuracy. We further performed molecular dynamics simulation and found three compounds that form stable interactions with key residues. These compounds could be used as a leads for further drug development and rational design of HIV-1 IN inhibitors. 相似文献
80.
O. Takahashi Y. Masuda A. Muroya T. Furuya 《SAR and QSAR in environmental research》2013,24(5-6):547-558
In general, the docking scoring tends to have a size dependence related to the ranking of compounds. In this paper, we describe a novel method of parameter optimization for docking scores which reduce the size dependence and can efficiently discriminate active compounds from chemical databases. This method is based on a simplified theoretical model of docking scores which enables us to utilize large amounts of data of known active and inactive compounds for a particular target without requiring large computational resources or a complicated procedure. This method is useful for making scoring functions for the identification of novel scaffolds using the knowledge of active compounds for a particular target or a customized scoring function for an interesting family of drug targets. 相似文献