Putative HIV-1 reverse transcriptase inhibitors: design, synthesis, in vitro evaluation and in silico analysis
Abstract
One of the most significant treatments for HIV-1 infection has been the combination of drugs targeting the HIV life cycle with the aim of preventing further destruction of the host immune system. This study addresses the design, synthesis, in vitro evaluation, and in silico analysis of putative HIV-1 reverse transcriptase (RT) inhibitors. The inhibitors comprise two structurally diverse components which are intended to bind separately to the enzyme allosteric site and to a location at, or close to, the polymerase active site. Therefore, the hydrophobic N-tritylated phalo-DL-phenylalanine derivatives (fluoro, chloro, bromo, iodo) have been coupled to 8-(6- aminohexyl) amino-adenosine-3',5'-cyclic monophosphate through N-hydroxysuccinimidecarbodiimide chemistry. Compounds were characterized by thin layer chromatography, UV spectroscopy, MALDI-TOF mass spectrometry and proton NMR spectrometry. A reverse transcriptase colorimetric assay kit, which features a sandwich ELISA protocol, based on biotin-avidin and digoxygenin-anti DIG interactions, was used for quantitative determination of the inhibitory effect of synthesized compounds on recombinant HIV-1 reverse transcriptase activity in vitro. Molecular docking simulations of the chimeric inhibitors within the allosteric site of HIV-1 RT, were performed using AutoDock Vina. The predicted binding associations were compared with laboratory findings on HIV-1 RT inhibition. Two dimensional representations of protein-ligand…
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Evidence Hub reads this as a thesis, done in cell cultures (in vitro) and computer models (in silico), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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