In Silico Prediction of Mutant HIV-1 Proteases Cleaving a Target Sequence

Background: Natural products have shown potent anti-HIV activity, but some of these also possess toxicity. The pharmacophoric fragments of these natural products have scope of combination with other pharmacophoric fragment and derivatization to reduce toxicity and increase the potency. Combination of natural product fragments from different classes of anti–HIV compounds may lead to a new class of potent anti–HIV agents. Objective: Design, in silico prediction of drug-likeness, ADMET properties and synthesis of pyrazol– pyridones. Evaluation of the anti–HIV–1 activity of synthesized pyrazol–pyridones. Methods: Pyrazol–pyridones were designed by combining reported anti–HIV pharmacophoric fragments. Designed molecules were synthesized after in silico prediction of drug-likeness and ADMET properties. Compounds were evaluated for activity against HIV–1VB59 and HIV–1UG070. Results: QED value of designed pyrazol–pyridones was greater than the known drug zidovudine. The designed compounds were predicted to be noncarcinogenic and nonmutagenic in nature. Seventeen novel pyrazol–pyridones were synthesized with good yield. Compound 6q and 6l showed activity with IC50 values 6.14 µM and 15.34 µM against HIV–1VB59 and 16.21 µM and 18.21 µM against HIV–1UG070, respectively. Conclusion: Compound 6q was found to be most potent among the synthesized compounds with a therapeutic index of 54.31against HIV–1VB59. This is the first report of anti–HIV–1 activity of pyrazol–pyridone class of compounds. Although the anti–HIV–1 activity of these compounds is moderate, this study opens up a new class for exploration of chemical space for anti–HIV–1 activity.

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Methoxyflavones from Marcetia taxifolia as HIV-1 Reverse Transcriptase Inhibitors

Natural Product Communications ◽

10.1177/1934578x1701201104 ◽

2017 ◽

Vol 12 (11) ◽

pp. 1934578X1701201 ◽

Cited By ~ 1

Author(s):

Joseph T Ortega ◽

María Luisa Serrano ◽

Alírica I Suárez ◽

Jani Baptista ◽

Flor H Pujol ◽

...

Keyword(s):

Virtual Screening ◽

Reverse Transcriptase ◽

Inhibitory Activity ◽

In Silico ◽

Antitumor Agents ◽

In Silico Prediction ◽

Reverse Transcriptase Inhibitors ◽

Hiv 1

Methoxyflavones are flavonoid widely distributed in plants and has been reported as potent antitumor agents and some of them have shown activity against HIV-1. In this work, two methoxyflavones isolated from Marcetia taxifolia were evaluated in vitro and in silico as HIV-1 inhibitors. Pentamethoxyflavone (5,3’-dihydroxy-3,6,7,8,4’-pentamethoxyflavone) (PMF) and Hexamethoxyflavone (5-Hydroxy-3,6,7,8,3’,4’-hexamethoxyflavone) (HMF) showed activity against HIV-1. The EC50 for HMF was 0.05 μM and 0.04 μM for PMF. The methoxyflavones also inhibited HIV-1 reverse transcriptase (RT), with an IC50 of 4.1 μM for HMF and 0.4 μM for PMF. PMF exhibited an IC50 lower than nevirapine (1.4 μM). These results are in agreement with the in silico prediction for the interaction of these flavonoids with RT. Furthermore, the effect of some methoxyflavones with different patterns of methoxylation was evaluated on RT activity in a virtual screening; found that the inhibitory activity was inversely proportional to the degree of methoxylation.

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Glycosylated Flavonoids from Psidium guineense as Major Inhibitors of HIV-1 Replication in vitro

Natural Product Communications ◽

10.1177/1934578x1701200712 ◽

2017 ◽

Vol 12 (7) ◽

pp. 1934578X1701200

Author(s):

Joseph T Ortega ◽

Omar Estrada ◽

Maria L Serrano ◽

Whendy Contreras ◽

Giovannina Orsini ◽

...

Keyword(s):

Antiviral Activity ◽

Reverse Transcriptase ◽

In Silico ◽

Biological Activities ◽

In Silico Prediction ◽

Flavonoid Quercetin ◽

Derivatives Of ◽

Anti Hiv ◽

Hiv 1

Flavonoids are present in practically all plants and many biological activities have been described for them. The flavonoid quercetin is a common molecule for which anti-HIV activity has been demonstrated. Avicularin and guajaverin are derivatives of quercetin with a glycoside substituent in their structure. In this work, a mixture of both derivatives was purified from an extract of Psidium guinense. The mixture exhibited activity against HIV-1 in vitro, with an IC50 of approximately 8.5 μg/mL, which compares favorably with the IC50 of 53 μg/mL of quercetin. The mixture also inhibited HIV-1 reverse transcriptase (RT), with an IC50 of 7.2 μM, compared to 0.6 μM for quercetin. These results are in agreement with the in silico prediction for the interaction of these flavonoids with RT and suggest that the glycosylic moiety could favor the transport of the compound into the cell. However, the glycosidic moiety might be cleaved intracellularly, being the resultant quercetin responsible for the antiviral activity.

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