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Bioanalysis Aug 2016Metabolite identification without radiolabeled compound is often challenging because of interference of matrix-related components.
BACKGROUND
Metabolite identification without radiolabeled compound is often challenging because of interference of matrix-related components.
RESULTS
A novel and an effective background subtraction algorithm (A-BgS) has been developed to process high-resolution mass spectral data that can selectively remove matrix-related components. The use of a graphics processing unit with a multicore central processing unit enhanced processing speed several 1000-fold compared with a single central processing unit. A-BgS algorithm effectively removes background peaks from the mass spectra of biological matrices as demonstrated by the identification of metabolites of delavirdine and metoclopramide.
CONCLUSION
The A-BgS algorithm is fast, user friendly and provides reliable removal of matrix-related ions from biological samples, and thus can be very helpful in detection and identification of in vivo and in vitro metabolites.
Topics: Algorithms; Animals; Bile; Chromatography, High Pressure Liquid; Delavirdine; Dopamine D2 Receptor Antagonists; Mass Spectrometry; Metoclopramide; Microsomes, Liver; Rats; Reverse Transcriptase Inhibitors; Time Factors
PubMed: 27460980
DOI: 10.4155/bio-2016-0101 -
Bioorganic & Medicinal Chemistry Aug 2015A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of...
A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50=0.24 , SI>1225), was more potent than delavirdine (EC50=0.66 μM, SI>67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.
Topics: Acetanilides; Anti-HIV Agents; Cell Line; Chemistry Techniques, Synthetic; Drug Discovery; Drug Evaluation, Preclinical; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Dynamics Simulation; Nitriles; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Triazoles
PubMed: 26162497
DOI: 10.1016/j.bmc.2015.06.048 -
European Journal of Medicinal Chemistry Feb 2016The development of novel NNRTIs with activity against variants of HIV-1RT is crucial for overcoming treatment failure. In the present study, a series of novel...
The development of novel NNRTIs with activity against variants of HIV-1RT is crucial for overcoming treatment failure. In the present study, a series of novel 6-substituted diarylpyridine derivatives targeting the entrance channel of the NNIBP of RT were designed through a molecular hybridization strategy. Encouragingly, these new diarylpyridine derivatives were found to be active against wild-type (WT) HIV-1 with an EC50 values ranging from 0.035 μM to 1.99 μM. Nearly half of them exhibited more potent inhibitory activities in cellular assays than the control drug nevirapine (NVP). Notably, three most promising compounds If (EC50 = 35 nM), Ia (EC50 = 43 nM) and IIa (EC50 = 41 nM) showed high potency against WT and were comparable to the reference drug delavirdine (DLV) (EC50 = 33 nM). Moreover, compounds Ib, IIb and IIh displayed effective activity against the most common clinically observed single and double-mutated HIV-1 strains in micromolar concentrations. In particular, the inhibition of IIb against the K103N mutation (EC50 = 49 nM), which confers resistance to a wide variety of NNRTIs, was about 140 times more effective than NVP (EC50 = 6.78 μM), 50 times more than DLV (EC50 = 2.48 μM) and about 3 times more than EFV (EC50 = 0.12 μM), indicating that the newly designed compounds have great potential to be further developed as new anti-HIV-1 agents. Preliminary structure-activity relationships (SARs) and molecular modeling of the new diarylpyridine derivatives were discussed in detail.
Topics: Anti-HIV Agents; Binding Sites; Drug Design; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Docking Simulation; Point Mutation; Pyridines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship
PubMed: 26802545
DOI: 10.1016/j.ejmech.2015.11.039 -
Chemical Biology & Drug Design Aug 2016With the continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed,...
Arylazolyl(azinyl)thioacetanilides: Part 19: Discovery of Novel Substituted Imidazo[4,5-b]pyridin-2-ylthioacetanilides as Potent HIV NNRTIs Via a Structure-based Bioisosterism Approach.
With the continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed, synthesized, and evaluated for their antiviral activities through combining bioisosteric replacement and structure-based drug design. Almost all of the title compounds displayed moderate to good activities against wild-type (wt) HIV-1 strain with EC50 values ranging from 0.059 to 1.41 μm in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 and 0.073 μm against wt HIV-1, respectively, which was much more effective than the control drug nevirapine (EC50 = 0.26 μm) and comparable to delavirdine (EC50 = 0.038 μm). In addition, one selected compound showed a remarkable reverse transcriptase inhibitory activity compared to nevirapine and etravirine. In the end of this manuscript, preliminary structure-activity relationships (SARs) and molecular modeling studies were detailedly discussed, which may provide valuable insights for further optimization.
Topics: Acetanilides; Anti-HIV Agents; Drug Discovery; Imidazoles; Molecular Structure; Pyridines; Reverse Transcriptase Inhibitors
PubMed: 26914186
DOI: 10.1111/cbdd.12751 -
Scientific Reports Oct 2015Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is an important target for antiviral therapy against acquired immunodeficiency syndrome. However,...
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. (1)H-(13)C 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 (13)C, were collected in the presence and absence of these NNRTIs. We found that the methyl (13)C 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.
Topics: Binding Sites; HIV Reverse Transcriptase; HIV-1; Humans; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Reverse Transcriptase Inhibitors
PubMed: 26510386
DOI: 10.1038/srep15806 -
European Journal of Medicinal Chemistry Mar 2015Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside...
Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 0.26 μM to 19 μM. Among them, 4a and 5a were found to be the two most active analogues possessing EC50 values of 0.26 μM and 0.32 μM respectively, comparable to delavirdine (DLV, EC50 = 0.54 μM) and nevirapine (NVP, EC50 = 0.31 μM) in a cell-based assay. Additionally, 9 compounds showed RT inhibitory activity superior to that of NVP. Moreover, some predicted drug-like properties of representative compounds 4a and 5a, as well as the structure-activity relationship (SAR) analysis were discussed in detail. The binding mode of compound 4a was investigated by molecular simulation studies.
Topics: Anti-HIV Agents; Chemistry Techniques, Synthetic; Computational Biology; Drug Design; HIV Reverse Transcriptase; HIV-1; Imidazoles; Molecular Docking Simulation; Protein Conformation; Pyrazines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship
PubMed: 25707013
DOI: 10.1016/j.ejmech.2015.02.022