scholarly journals Molecular docking based design of Inhibitors for viral Non-Nucleosidase as potential anti-retroviral agents

2020 ◽  
Vol 16 (10) ◽  
pp. 736-741
Author(s):  
Ahmed Alharbi ◽  
Keyword(s):  
Molecular Docking ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Active Site ◽  
Viral Protein ◽  
Protein Targeting ◽  
Antiretroviral Drugs ◽  
New Chemical Entities ◽  
Electronic Parameters ◽  
Rt Inhibitors

Reverse Transcriptase (RT) inhibitors are highly promising agents for use as an effective anti-retroviral therapy (HAART) which is typically a combination of three or four antiretroviral drugs. We used direct drug design approach to discover new chemical entities for the target protein. The validated template of the protein targeting reverse transcriptase PDB ID 1JKH was extracted for three sites hydrophobic, steric, and electronic parameters explain the interactions at the active site by the inhibitors. We used the Zinc library of compounds to explore the possible leads for HAART through RT inhibition. We report 12 new chemical entities with possible activity against the targeted viral protein. These leads will provide new therapeutic means in antiretroviral therapy.

scholarly journals Rational in silico drug design of HIV-RT inhibitors through G-QSAR and molecular docking study of 4-arylthio and 4-aryloxy-3-iodopyridine-2(1-H)-one derivative

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Debadash Panigrahi ◽  
Amiyakanta Mishra ◽  
Susanta Kumar Sahu
Keyword(s):  
Molecular Docking ◽  
Reverse Transcriptase ◽  
Active Site ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Immunodeficiency Virus ◽  
Qsar Models ◽  
Hiv Rt ◽  
Rt Inhibitors ◽  
Anti Hiv

Abstract Background Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Antiretroviral therapy (ART) against HIV infection offers the promise of controlling disease progression and prolonging the survival of HIV-infected patients. Reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In this direction, by using group-based QSAR study (G-QSAR), identification of the structural need for the development of lead structure with reverse transcriptase inhibition on 97 reported structures was carried out. Docking analysis was performed further and suggested the structural properties required for binding affinity with the receptor. The molecules in the data set were fragmented into six (R1, R2, R3, R4, R5, and R6) by applying the fragmentation pattern. Three G-QSAR models were selected based on the statistical significance of the model. The molecular docking study was performed to explain the structural properties required for the design of potent HIV-RT inhibitors. Results The statistically validated QSAR models reveal the presence of higher hydrophobic groups containing single-bonded –Br atom, 2 aromatic bonded –NH group with less electronegativity, and entropic interaction fields at R2 essential for better anti-HIV activity. The presence of a lipophilic group at R3, oxygen and sulfur connected with two aromatic bonds at R4, and –CH3 group at R5 was fruitful for reverse transcriptase inhibition. Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond, Van der Waal’s, charge, aromatic, and π–π interactions with residues present at the active site. Conclusion The results of the generated models provide significant site-specific insight into the structural requirements for reverse transcriptase inhibition during the design and development of novel anti-HIV compounds. Molecular docking study revealed the binding interaction between the ligand and the receptor which gave insight towards the structure-based design for the discovery of more potent compounds with better activity against HIV infection.

A Combined approach of Pharmacophore Modeling, QSAR Study, Molecular Docking and in silico ADME/Tox prediction of 4-Arylthio & 4- Aryloxy-3- Iodopyridine-2(1H)-one analogs to identify potential Reverse Transcriptase inhibitor: Anti-HIV agents

2020 ◽  
Vol 17 ◽  
Author(s):  
Debadash Panigrahi ◽  
Amiyakanta Mishra ◽  
Susanta Kumar Sahu ◽  
Mohd. Afzal Azam ◽  
C.M. Vyshaag
Keyword(s):  
Molecular Docking ◽  
Reverse Transcriptase ◽  
Active Site ◽  
3D Qsar ◽  
Qsar Model ◽  
Pharmacophore Modeling ◽  
Reverse Transcriptase Inhibitors ◽  
Rt Inhibitors ◽  
Anti Hiv ◽  
Exclusion Method

Background: Reverse transcriptase is an important therapeutic target to treat AIDS caused by the Human Immunodeficiency Virus (HIV). Despite many effective anti-HIV drugs, reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In the present work, we have expedited the use of different computational modules and presented an easy, cost-effective and high throughput screening method to identify potential reverse transcriptase inhibitors. Methods: A congeneric series of 4-Arylthio & 4-Aryloxy-3- Iodopyridine-2(1H)-one analogs having anti-HIV activity were subjected to structure-based 2D, 3D QSAR, Pharmacophore Modeling, and Molecular Docking to elucidate the structural properties required for the design of potent HIV-RT inhibitors. Prediction of preliminary Pharmacokinetic and the Drug Likeliness profile was performed for these compounds by in silico ADME study. Results: The 2D and 3D- QSAR models were developed by correlating two and three-dimensional descriptors with activity (pIC50) by sphere exclusion method and k-nearest neighbor molecular field analysis approach, respectively. The significant 2D- QSAR model developed by Partial Least Square associated with the Sphere Exclusion method (PLS-SE) having r2 and q2 values 0.9509 and 0.8038 respectively. The 3D-QSAR model by Step Wise variable selection method (SW-kNN MFA) is more significant which has a cross-validated squared correlation coefficient q2= 0.8509 and a non-cross-validated correlation coefficient pred_r2= 0.8102. The pharmacophore hypothesis was developed which comprised 5 features includes 3 aliphatic regions (Ala), 1 H-bond donor (HDr) and 1 H-bond acceptor (HAc). Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond and π - π interaction with LYS-101, LYS-103, TYR- 181, TYR-188 and TRP-229 residues present at the active site. All the candidates with good bioavailability and ADMET drug likeliness properties. Conclusion: The results of the present work provide more useful information and important structural insights for the discovery, design of novel and potent reverse transcriptase inhibitors with high therapeutic windows in the future.

Neuropsychiatric adverse effects of HIV antiviral medication

2017 ◽  
Vol 41 (S1) ◽  
pp. S697-S698
Author(s):  
S. Nascimento ◽  
M. Mendes ◽  
C. Solana ◽  
M. Croca ◽  
J. Reis
Keyword(s):  
Antiretroviral Therapy ◽  
Adverse Effects ◽  
Reverse Transcriptase ◽  
Opportunistic Infections ◽  
Antiretroviral Drugs ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Neuropsychiatric Complications ◽  
Competing Interest ◽  
Neuropsychiatric Adverse Effects

IntroductionHIV (human immunodeficiency virus) infection is related to several neuropsychiatric complications, such as dementia, encephalopathy, psychosis, as well as, opportunistic infections of the central nervous system (CNS). The discovery of antiretroviral therapy (ART) has limited these conditions and extended the life span of infected patients into a chronic illness, but it is also associated with neuropsychiatric adverse effects.ObjectivesTo review the literature on the most common neuropsychiatric complications of the ART, since it can be difficult to distinguish drugs toxicity, the effects of the virus, immune system and psycho-social events.MethodsThe authors have conducted an online search in PubMed with the terms: “Psychiatry”, “HIV”, “adverse effects” and “antiretroviral drugs” from 2011 until 2016. From the outcome were collected, analyzed and summarized the articles considered to be relevant.ResultsThe antiretroviral therapy (ART) are associated with a numerous adverse effects on the central and peripheral nervous systems, as well as, metabolic, gastrointestinal, cardiac, and other toxicities. The neuropsychiatric effects are common and highly variable, including depression, cognitive impairment and sleep disturbance. The nucleoside reverse transcriptase inhibitors and the non-nucleoside reverse transcriptase inhibitors are one of the two classes of antiviral drugs most frequently associated with neuropsychiatric complications.ConclusionsThe occurrence of new-onset conditions related to ART makes it difficult to determine the association between psychiatric disorders and ART adverse effects, and given the fact that patients commit to lifelong therapy, as well as, they can diminish quality of life; it makes these assessment important in treating these conditions.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals HIV-1 CRF63_02A6 models as a tool for evaluating efficacy of developing antiretroviral drugs

2020 ◽  
Vol 10 (4) ◽  
pp. 769-774
Author(s):  
D. P. Zyryanova ◽  
N. V. Bogacheva ◽  
A. V. Totmenin ◽  
N. M. Gashnikova
Keyword(s):  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Federal District ◽  
Antiretroviral Drugs ◽  
Infection Process ◽  
Reverse Transcriptase Inhibitors ◽  
Infectious Molecular Clones ◽  
Hiv 1

Highly active antiretroviral therapy (HAART) allows not only to control the infection process in certain patient, but also to reduce a risk of HIV infection spreading in general, so that one of the goals for international community fighting against HIV-spread is to maximize coverage of infected subjects with HAART. Antiretroviral therapy in HIV infection is administered lifelong, so that therapeutic efficacy may be lowered due to emergence of resistant HIV-1 variants. Currently, development of new antiretroviral drugs is currently underway throughout the world, therefore standard HIV-1 models are demanded to evaluate antiviral efficacy of promising drugs. To reliably assess drug efficiency regarding Russiawide HIV-1 variants, HIV-1 genovariants widespread in Russia should be used as a virus model. A recently emerged recombinant form of CRF63_02A6 HIV-1 is spread in Russia being currently a dominant variant detected among HIV-infected individuals in an extended region of the Siberian Federal District: in the Novosibirsk, Tomsk, Omsk, Kemerovo Regions, Krasnoyarsk and Altai Krai. We have obtained CRF63_02A6 infectious isolates of HIV-1, one of which contains mutations, reducing the sensitivity to the applied inhibitors of the virus reverse transcriptase. In addition, we constructed infectious molecular clones based on HIV-1 CRF63_02A6 variants with an affinity for CCR5 coreceptors and CXCR4. Infectious isolates and molecular clones CRF63_02A6 tested as models for assessing efficacy of antiretroviral drugs using the example of the drug “Efavirenz”. The fifty percent inhibitory concentration determined on the models of HIV-1 infectious molecular clones and HIV-1 isolate 18RU7056 ranged from 0.00027 pg/ml to 0.00046 pg/ml being in agreement with data published elsewhere. Concentrations of “Efavirenz” used in the study did not suppress the replication of HIV-1 12RU6987, which is resistant to non-nucleoside reverse transcriptase inhibitors, which confirms the decrease in the sensitivity of HIV-1 12RU6987 to “Efavirenz” by no less than 10,000 times. Thus, our data demonstrate that CRF63_02A6 HIV-1 isolated strains and infectious molecular clones are relevant and complementary tools for assessing efficacy of developing drugs aimed at suppressing HIV-1, including non-nucleoside-resistant virus reverse transcriptase inhibitors.

scholarly journals Transmitted Drug Resistance in Antiretroviral Therapy-Naive Persons With Acute/Early/Primary HIV Infection: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunxiang Guo ◽  
Yaxin Wu ◽  
Yang Zhang ◽  
Xinchao Liu ◽  
Aixin Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Reverse Transcriptase ◽  
Meta Analysis ◽  
Antiretroviral Drugs ◽  
Cochrane Library ◽  
Transmitted Drug Resistance ◽  
Reverse Transcriptase Inhibitors ◽  
Primary Hiv Infection

Background: The widespread use of antiretroviral therapy (ART) has raised concerns about the emergence of HIV transmitted drug resistance (TDR). Acute HIV infection (AHI) was the most appropriate time to detect the spread of TDR. In this meta-analysis, our purpose was to evaluate the level of TDR in ART-naive patients with primary HIV infection (PHI)/AHI/early HIV infection (EHI) and to describe the critical drug-resistant mutations.Methods: We systematically searched the literature between January 1, 2008, and April 30, 2021, in PubMed, Web of Science, Embase, and the Cochrane Library. To evaluate the overall prevalence of TDR, we extracted raw data and analyzed prevalence estimates using Stata SE.Results: The data of this meta-analysis come from 12 observational studies, covering 3,558 ART-naive individuals with PHI, AHI, or EHI. The overall prevalence of HIV-TDR is 9.3% (95% CI: 6.8%–11.8%, I2 = 81.1%, in 11 studies). The prevalence of resistance by drug class is the highest for the nonnucleoside reverse transcriptase inhibitors (NNRTIs) at 5.7% (95% CI: 2.9%–8.5%, I2 = 96.6%, in 11 studies), followed by nucleoside reverse transcriptase inhibitors (NRTIs) at 3.4% (95% CI: 1.8%–5.0%, I2 = 86.3%, in 10 studies) and protease inhibitors (PIs) at 3.3% (95% CI: 2.7%–3.9%, I2 = 15.6%, in 10 studies). The prevalence of TDR to integrase inhibitors (INIs) is 0.3% (95% CI: 0.1%–0.7%, I2 = 95.9%, in three studies), which is the lowest among all antiretroviral drugs.Conclusion: The overall prevalence of TDR is at a moderate level among AHI patients who have never received ART. This emphasizes the importance of baseline drug resistance testing for public health surveillance and guiding the choice of ART. In addition, the prevalence of TDR to NNRTIs is the highest, while the TDR to INIs is the lowest. This may guide the selection of clinical antiretroviral drugs.

scholarly journals Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels as compared with therapy based on protease inhibitors

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Alexander O Pasternak ◽  
Jelmer Vroom ◽  
Neeltje A Kootstra ◽  
Ferdinand WNM Wit ◽  
Marijn de Bruin ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Antiretroviral Drugs ◽  
Combination Antiretroviral Therapy ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Reverse Transcriptase Inhibitor ◽  
Rna And Dna

BACKGROUND: It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress HIV replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).METHODS: CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n=100, n=124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically-measured adherence to ART.RESULTS: In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho=0.70 and rho=0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj=0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj=0.048 and padj=0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.CONCLUSIONS: All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.

QSAR and Docking Studies of DATA Analogues as HIV-1 Reverse Transcriptase Inhibitors

2018 ◽  
Vol 16 (2) ◽  
pp. 153-159 ◽  
Author(s):  
Jianbo Tong ◽  
Shan Lei ◽  
Pei Zhan ◽  
Shangshang Qin ◽  
Yang Wang
Keyword(s):  
Biological Activity ◽  
Molecular Docking ◽  
Reverse Transcriptase ◽  
3D Qsar ◽  
Docking Studies ◽  
Reverse Transcriptase Inhibitors ◽  
Electronic Density ◽  
Topomer Comfa ◽  
Rt Inhibitors ◽  
Hiv 1

Background: Acquired Immunodeficiency Syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV) has seriously threatened human health, so development of new, selective and safe non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) remains a high priority for medical research. Diaryltriazine (DATA) have been identified as a new class of potent nonnucleoside HIV-1 Reverse Transcriptase (RT) inhibitors. The study deals with Topomer CoMFA (Comparative Molecular Field Analysis) and molecular docking to explore the important features of DATA analogues for exerting potent HIV-1 RT inhibitors activity. Methods: In this work, 40 DATA analogues were studied using a combination of molecular modeling techniques including Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR), molecular docking, and Topomer CoMFA were used to build 3D-QSAR models. Results: The results show that the Topomer CoMFA analysis has the cross-validation q2 = 0.800, SDCV = 0.45, the non-cross-validated r2 = 0.958, SD = 0.21, and the correlation coefficient of external validation Q2 ext = 0.965 showed that the model is reasonable and credible, and has a good predictive ability. Then binding mode pattern of the compounds to the binding site of enzyme was confirmed and the mechanism of drug and acceptor was studied by docking studies, the results showed that the drug and GLU138, LYS101, THR139 sites have an obvious function, these researches have provided an useful information for designing more effective HIV-1IN inhibitors. Conclusion: A series of 40 DATAs analogues was subjected to a 3D-QSAR study. Using Topomer CoMFA 3D-QSAR method built model, and the model has shown a good predictive and statistical validation. Substituent with low electronic density in the R5 and R3 positions and substituent with high electronic density in the R2 and C2 positions will increase the biological activity, small substituent on R4 positions and naphthyloxy as the spacer group C6 substituent hydrophobic will increase biological activity. This effect is supported by Topomer CoMFA contour map and docking results of HIV-1RT inhibition active site, the results of the 3D-QSAR and docking analyses have provided a guide for the synthesis of new putative inhibitors for HIV-1RT to improved inhibitory activity.

scholarly journals Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels as compared with therapy based on protease inhibitors

2021 ◽  
Author(s):  
Alexander O. Pasternak ◽  
Jelmer Vroom ◽  
Neeltje A. Kootstra ◽  
Ferdinand W.N.M. Wit ◽  
Marijn de Bruin ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Antiretroviral Drugs ◽  
Combination Antiretroviral Therapy ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Reverse Transcriptase Inhibitor ◽  
Rna And Dna

AbstractBACKGROUNDIt remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress HIV replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).METHODSCA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n=100, n=124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically-measured adherence to ART.RESULTSIn both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho=0.70 and rho=0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj=0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj=0.048 and padj=0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.CONCLUSIONSAll current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.

Sign in / Sign up

Export Citation Format

Share Document