Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is an important target for antiviral therapy against acquired immunodeficiency syndrome. However, the efficiency of available drugs is impaired most typically by drug-resistance mutations in this enzyme. In this study, we applied a nuclear magnetic resonance (NMR) spectroscopic technique to the characterization of the binding of HIV-1 RT to various non-nucleoside reverse transcriptase inhibitors (NNRTIs) with different activities, i.e., nevirapine, delavirdine, efavirenz, dapivirine, etravirine, and rilpivirine. 1H-13C heteronuclear single-quantum coherence (HSQC) spectral data of HIV-1 RT, in which the methionine methyl groups of the p66 subunit were selectively labeled with 13C, were collected in the presence and absence of these NNRTIs. We found that the methyl 13C chemical shifts of the M230 resonance of HIV-1 RT bound to these drugs exhibited a high correlation with their anti-HIV-1 RT activities. This methionine residue is located in proximity to the NNRTI-binding pocket but not directly involved in drug interactions and serves as a conformational probe, indicating that the open conformation of HIV-1 RT was more populated with NNRTIs with higher inhibitory activities. Thus, the NMR approach offers a useful tool to screen for novel NNRTIs in developing anti-HIV drugs.
Six new 14-membered ring cyclopeptide alkaloids, cambodines A–F (1–6), and two known compounds, frangufoline (7) and lotusanine B (8), were isolated from the root bark extract ofZiziphus cambodianaPierre.
Two-layered ONIOM calculations were performed in order to compare the binding of efavirenz (EFV) to the HIV-1 RT binding pocket of both wild type (WT) and K103N enzymes. The K103N mutation reduces the binding affinity of the inhibitor by 5.81 kcal mol À1 as obtained from the ONIOM2 (B3LYP/ 6-31G(d,p):PM3) method. These indicate that the loss of binding energy to K103N mutation can attribute to a weakened attractive interaction between the drug and residues surrounding in the binding pocket. The deformation of the K103N binding pocket requires more energy for structural rearrangement than that of the WT by approximately 4.0 kcal mol :1 . Moreover, the pairwise energies perfectly demonstrate that the K103N mutation affects on the loss of the interaction energy. In addition, the main influences are due to residues surrounding in the binding pocket; K101, K102, S105, V179, W229, P236 and E138. In particular, two residues; K101 and S105, established hydrogen bondings with the inhibitor. ONIOM calculations, resulting in the details of binding energy, interaction energy and deformation energy can be used to identify the key interaction and structural requirements of more potent HIV-1 RT inhibitor.
In this study, amino-oxy-diarylquinolines were designed using structure-guided molecular hybridization strategy and fusing of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), etravirine (ETV, TMC125) and rilpivirine (RPV, TMC278). The anti-HIV-1 reverse transcriptase (RT) activity was evaluated using standard ELISA method, and the cytotoxic activity was performed using MTT and XTT assays. The primary bioassay results indicated that 2-amino-4-oxy-diarylquinolines possess moderate inhibitory properties against HIV-1 RT. Molecular docking results showed that 2-amino-4-oxy-diarylquinolines 8(a-d) interacted with the Lys101 and His235 residue though hydrogen bonding and interacted with Tyr318 residue though π-π stacking in HIV-1 RT. Furthermore, 8a and 8d were the most potent anti-HIV agents among the designed and synthesized compounds, and their inhibition rates were 34.0% and 39.7% at 1 µM concentration. Interestingly, 8a was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC50 of 4.63±0.62 µg/mL, which was similar with that in EFV and TMC278 (IC50 7.76±0.37 and 1.57±0.20 µg/ml, respectively). Therefore, these analogs of the synthesized compounds can serve as excellent bases for the development of new anti-HIV-1 agents in the near future.
Phosphomevalonate kinase (PMK) phosphorylates mevalonate-5-phosphate (M5P) in the mevalonate pathway, which is the sole source of isoprenoids and steroids in humans. We have identified new PMK inhibitors with virtual screening, using Autodock. Promising hits were verified and their affinity measured using NMR-based 1H-15N Heteronuclear Single Quantum Coherence (HSQC) chemical shift perturbation and fluorescence titrations. Chemical shift changes were monitored, plotted, and fitted to obtain dissociation constants (Kd). Tight binding compounds with Kd’s ranging from 6–60 µM were identified. These compounds tended to have significant polarity and negative charge, similar to the natural substrates (M5P and ATP). HSQC crosspeak changes suggest that binding induces a global conformational change, such as domain closure. Compounds identified in this study serve as chemical genetic probes of human PMK, to explore pharmacology of the mevalonate pathway, as well as starting points for further drug development.
Hydrogen peroxide (H2O2), an oxidizer produced by water radiolysis, is considered one of the main contributors to corrosion of the stainless steel (SS) components in the cooling system of nuclear reactors. The detailed understanding of this chemical system is however still missing. The present research aimed to study the effects of H2O2 on 304 SS. The surface morphology and the chemical composition of the SS specimens after experiment were examined using Scanning Electron Microscope – Energy Dispersive X-ray (SEM-EDX). The change in atomic % of Fe, Cr, Ni, and O as a function of temperature will be reported. The corrosion type and possible corrosion products will be proposed and discussed.
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