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  • Penicillin G Sodium sale It is apparent from the data in tha

    2022-06-18

    It is apparent from the data in that none of the ligands exhibits significant toxicity as determined by the viability of human embryonic kidney (HEK 293) cells at a concentration of 100 μM. It is also apparent from the data in and that a number of the ligands inhibit the HIV-1 IN enzyme. However, their inhibition levels, as evidenced by the IC data in (for which chicoric Penicillin G Sodium sale was used as the standard), vary significantly from ligand to ligand and a number of structure-activity trends are apparent. In order to rationalize the possible binding mechanism of our compounds, the most active ligand was selected for docking studies. The molecular docking study was performed with Autodock vina, and Accelrys Discovery Studio Visualizer 3.5 was used for visualisation and analysis. The Prototype Foamy Virus integrase (PFV-IN) has been demonstrated to be a good model for the HIV-1 IN core domain and, consequently, the PFV-IN structure with two magnesium cations and a double chain DNA (PDB: ) was used as the receptor for docking analysis. In order to validate the docking protocol, the co-crystallized ligand raltegravir was re-docked in the active site of the crystal structure of integrase (PDB: ). The predicted binding interactions of the ()-enantiomer of within the HIV-1 IN active site are illustrated in . Thus, two of the ligand’s phenolic oxygens chelate with one Mg cation, while the imine nitrogen atom and the β-hydroxyl group are orientated to chelate the second Mg cation. Potential ligand-receptor hydrogen-bonding interactions are also evident between the -phenolic hydroxyl hydrogen and the Glu221 carbonyl oxygen, and between the β -hydroxyl hydrogen and Asp128 and Asp185. illustrates superposition of the ligand and the co-crystalized raltegravir in the HIV-1 IN receptor and reveals how well the ligand mimics the chelation of both Mgcations by raltegravir . The 4-arylimino-3-hydroxybutanoic acids are readily accessible a one-step reaction using commercially available starting materials. In addition to showing insignificant toxicity against HEK 293 at a concentration of 100 µM, many of the ligands show encouraging activity against HIV-1 IN. Perhaps, even more importantly, HIV-1 inhibition activity appears to be very sensitive to small changes in the nature and pattern of the ring substituents, suggesting that the 4-arylimino-3-hydroxybutanoic acid system could serve as a promising scaffold in the development of novel HIV-1 IN inhibitors. Bioassay protocols have been reported previously. Experimental methods, data and NMR spectra are provided in the . Acknowledgements The authors thank Rhodes University and the South African Medical Research Council (SAMRC) for generous financial support. This research project was funded by the South African Medical Research Council (SAMRC) with funds from National Treasury under its Economic Competitiveness and Support Package.
    Background Before the introduction of highly active anti-retroviral therapy (HAART), HIV-positive patients were treated with mono- or dual-therapy that resulted in the rapid emergence of HIV drug resistance [1], [2]. This resulted in a large population of HIV-infected patients with detectable, drug-resistant virus that could be transmitted to uninfected individuals. Transmitted drug resistance (TDR) in HIV-infected patients in the UK and EU has decreased since the early 2000s to between 5% and 10% depending on the patient risk group [3], [4], [5]. TDR typically involves mutations that affect nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside transcriptase inhibitors (NNRTIs) and to lesser extent protease inhibitors (PIs), as these were the front-line agents until relatively recently. The British HIV Association (BHIVA) guidelines therefore recommend performing baseline HIV resistance testing on all new diagnosis prior to commencing HAART [6]. Specifically, investigating the pol region as this encodes the drug targets, the viral protease and reverse transcriptase.