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Journal of Biomolecular Structure &... Feb 2024The dengue virus (DENV) infects approximately 400 million people annually worldwide causing significant morbidity and mortality. Despite advances in understanding the...
The dengue virus (DENV) infects approximately 400 million people annually worldwide causing significant morbidity and mortality. Despite advances in understanding the virus life cycle and infectivity, no specific treatment for this disease exists due to the lack of therapeutic drugs. In addition, vaccines available currently are ineffective with severe side effects. Therefore, there is an urgent need for developing therapeutics suitable for effective management of DENV infection. In this study, we adopted a drug repurposing strategy to identify new therapeutic use of existing FDA approved drug molecules to target DENV2 non-structural proteins NS3 and NS5 using computational approaches. We used Drugbank database molecules for virtual screening and multiple docking analysis against a total of four domains, the NS3 protease and helicase domains and NS5 MTase and RdRp domains. Subsequently, MD simulations and MM-PBSA analysis were performed to validate the intrinsic atomic interactions and the binding affinities. Furthermore, the internal dynamics in all four protein domains, in presence of drug molecule binding were assessed using essential dynamics and free energy landscape analyses, which were further coupled with conformational dynamics-based clustering studies and cross-correlation analysis to map the regions that exhibit these structural variations. Our comprehensive analysis identified tolcapone, cefprozil, delavirdine and indinavir as potential inhibitors of NS5 MTase, NS5 RdRp, NS3 protease and NS3 helicase functions, respectively. These high-confidence candidate molecules will be useful for developing effective anti-DENV therapy to combat dengue infection.Communicated by Ramaswamy H. Sarma.
PubMed: 38334186
DOI: 10.1080/07391102.2024.2313161 -
Chemical Biology & Drug Design Jan 2024Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations... (Review)
Review
Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART).
Topics: Humans; Reverse Transcriptase Inhibitors; Anti-HIV Agents; HIV-1; Molecular Docking Simulation; HIV Infections; Acquired Immunodeficiency Syndrome; HIV Reverse Transcriptase
PubMed: 37817296
DOI: 10.1111/cbdd.14372 -
Irish Journal of Medical Science Feb 2024The COVID-19 pandemic has been recognized as severe acute respiratory syndrome, one of the worst and disastrous infectious diseases in human history. Until now, there...
OBJECTIVE
The COVID-19 pandemic has been recognized as severe acute respiratory syndrome, one of the worst and disastrous infectious diseases in human history. Until now, there is no cure to this contagious infection although some multinational pharmaceutical companies have synthesized the vaccines and injecting them into humans, but a drug treatment regimen is yet to come.
AIM
Among the multiple areas of SARS-CoV-2 that can be targeted, protease protein has significant values due to its essential role in viral replication and life. The repurposing of FDA-approved drugs for the treatment of COVID-19 has been a critical strategy during the pandemic due to the urgency of effective therapies. The novelty in this work refers to the innovative use of existing drugs with greater safety, speed, cost-effectiveness, broad availability, and diversity in the mechanism of action that have been approved and developed for other medical conditions.
METHODS
In this research work, we have engaged drug reprofiling or drug repurposing to recognize possible inhibitors of protease protein 6M03 in an instantaneous approach through computational docking studies.
RESULTS
We screened 16 FDA-approved anti-viral drugs that were known for different viral infections to be tested against this contagious novel strain. Through these reprofiling studies, we come up with 5 drugs, namely, Delavirdine, Fosamprenavir, Imiquimod, Stavudine, and Zanamivir, showing excellent results with the negative binding energies in Kcal/mol as - 8.5, - 7.0, - 6.8, - 6.8, and - 6.6, respectively, in the best binding posture. In silico studies allowed us to demonstrate the potential role of these drugs against COVID-19.
CONCLUSION
In our study, we also observed the nucleotide sequence of protease protein consisting of 316 amino acid residues and the influence of these pronouncing drugs over these sequences. The outcome of this research work provides researchers with a track record for carrying out further investigational procedures by applying docking simulations and in vitro and in vivo experimentation with these reprofile drugs so that a better drug can be formulated against coronavirus.
Topics: Humans; COVID-19; Antiviral Agents; SARS-CoV-2; Drug Repositioning; Pandemics; Molecular Docking Simulation; Peptide Hydrolases
PubMed: 37515684
DOI: 10.1007/s11845-023-03473-9 -
European Journal of Medicinal Chemistry Feb 2023The hybrids of delavirdine and piperdin-4-yl-aminopyrimidine (DPAPYs) were designed from two excellent HIV-1 NNRTIs delavirdine and piperidin-4-yl-aminopyrimidine via...
The hybrids of delavirdine and piperdin-4-yl-aminopyrimidine (DPAPYs) were designed from two excellent HIV-1 NNRTIs delavirdine and piperidin-4-yl-aminopyrimidine via molecular hybridization. The target compounds 4a-r were prepared and evaluated for their cellular anti-HIV activities and cytotoxicities as well as the inhibitory activities against HIV-1 reverse transcriptase (RT). All the newly synthesized compounds demonstrated moderate to excellent potency against wild-type (WT) HIV-1 with EC values in a range of 5.7 to 0.0086 μM and against RT with IC values ranging from 12.0 to 0.11 μM, indicating that the DPAPYs were specific RT inhibitors. Among all, 4d displayed the most potent activity against WT HIV-1 (EC = 8.6 nM, SI = 2151). Gratifyingly, it exhibited good to excellent potency against the single HIV-1 mutants L100I, K103N, Y181C, Y188L, E138K, as well as the double mutant F227L + V106A. Furthermore, the preliminary structure-activity relationships were summarized, molecular modeling was conducted to explore the binding mode of DPAPYs and HIV-1 RT, and their physicochemical properties were also predicted.
Topics: Anti-HIV Agents; Delavirdine; Drug Design; HIV Reverse Transcriptase; HIV-1; Reverse Transcriptase Inhibitors; Structure-Activity Relationship
PubMed: 36640458
DOI: 10.1016/j.ejmech.2023.115114 -
Computational Biology and Chemistry Jun 2022A series of quinoline derivatives has been designed, synthesized and screened for their anti-HIV properties. The drug-like properties of compounds were evaluated first...
A series of quinoline derivatives has been designed, synthesized and screened for their anti-HIV properties. The drug-like properties of compounds were evaluated first and then molecular docking using DS v20.1.0.19295 software showed that the compounds behaved as non-nucleoside reverse transcriptase inhibitors (NNRTIs) while interacting at the allosteric site of target HIV-RT protein (PDB:3MEC). The docking results revealed that all compounds formed hydrogen bonds with Lys101, Lys103, Val179, Tyr188, Gln190, Gly190, Pro225, Phe227, and Tyr318, and showed π-interaction with Tyr188 and Tyr318. TOPKAT (Toxicity Prediction by Komputer Assisted Technology) results confirmed that the compounds were found to be less toxic than the reference drugs. Density functional theory (DFT) analysis was performed to assess the binding affinity of all compounds. Further, molecular dynamics (MD) simulations were performed on compound 6 and delavirdine with HIV-RT enzyme. Comprehensive MD analyses showed a similar pattern of conformational stability and flexibility in both the complexes suggesting alike inhibitory action. The hydrogen-bonding interactions and the binding energy of active-site residues for the compound 6 complex revealed strong inhibitory activity than the reference (delavirdine) complex. Thus, the compound 6 might act as a potential inhibitor against HIV-RT. Overall, this study revealed that compound 6 (5-hydroxy-N-(4-methyl-2-oxo-1,2-dihydroquinolin-8-yl) thiophene-2-sulfonamide) has prudent anti-HIV activity against both HIV-1 (SI = 2.65) and HIV-2 (SI = 2.32) that can further be utilised in drug discovery against HIV virus.
Topics: Catalytic Domain; Delavirdine; Drug Design; HIV Infections; HIV Reverse Transcriptase; Humans; Molecular Docking Simulation; Quinolines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship
PubMed: 35395595
DOI: 10.1016/j.compbiolchem.2022.107675 -
Frontiers in Pharmacology 2021We aimed to develop a physiological-based pharmacokinetic and dipepidyl peptidase 4 (DPP-4) occupancy model (PBPK-DO) characterized by two simultaneous simulations to...
Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy.
We aimed to develop a physiological-based pharmacokinetic and dipepidyl peptidase 4 (DPP-4) occupancy model (PBPK-DO) characterized by two simultaneous simulations to predict pharmacokinetic (PK) and pharmacodynamic changes of saxagliptin and metabolite M2 in humans when coadministered with CYP3A4 inhibitors or inducers. Ketoconazole, delavirdine, and rifampicin were selected as a CYP3A4 competitive inhibitor, a time-dependent inhibitor, and an inducer, respectively. Here, we have successfully simulated PK profiles and DPP-4 occupancy profiles of saxagliptin in humans using the PBPK-DO model. Additionally, under the circumstance of actually measured values, predicted results were good and in line with observations, and all fold errors were below 2. The prediction results demonstrated that the oral dose of saxagliptin should be reduced to 2.5 mg when coadministrated with ketoconazole. The predictions also showed that although PK profiles of saxagliptin showed significant changes with delavirdine (AUC 1.5-fold increase) or rifampicin (AUC: a decrease to 0.19-fold) compared to those without inhibitors or inducers, occupancies of DPP-4 by saxagliptin were nearly unchanged, that is, the administration dose of saxagliptin need not adjust when there is coadministration with delavirdine or rifampicin.
PubMed: 34737703
DOI: 10.3389/fphar.2021.746594 -
Drug Design, Development and Therapy 2021Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological... (Review)
Review
Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological activity, which has led to the discovery of numerous broad-spectrum therapeutic agents. In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer's), ciclopirox (ringworm and athlete's foot), crizotinib (cancer), nifedipine (Raynaud's syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. Their remarkable therapeutic applications have encouraged researchers to prepare a larger number of biologically active compounds decorated with pyridine or dihydropyridine, expandeing the scope of finding a cure for other ailments. It is thus anticipated that myriad new pharmaceuticals containing the two heterocycles will be available in the forthcoming decade. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development.
Topics: Animals; Chemistry, Pharmaceutical; Dihydropyridines; Drug Design; Drug Development; Humans; Pyridines; Structure-Activity Relationship
PubMed: 34675489
DOI: 10.2147/DDDT.S329547 -
Current Topics in Medicinal Chemistry 2022Acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV), is one of the leading causes of human deaths. The advent of different... (Review)
Review
Acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV), is one of the leading causes of human deaths. The advent of different anti-HIV drugs has turned AIDS/HIV from a deadly infection to chronic and manageable disease. However, the development of multidrug-resistant viruses, along with the severe side effects of anti-HIV agents, has compromised their efficacy and limited the treatment options. Indoles, the most common frameworks in the bioactive molecules, represent attractive scaffolds for designing and developing novel drugs. Indole derivatives are potent inhibitors of HIV enzymes such as reverse transcriptase, integrase, and protease. Furthermore, some indole-based agents, like delavirdine, have already been applied in clinics or are under clinical evaluations for the treatment of AIDS/HIV, revealing that indole moiety is a useful template for the development of anti-HIV agents. This review focuses on the recent advancement in indole derivatives, including indole alkaloids, hybrids, and dimers with anti-HIV potential, covering articles published between 2010 and 2020. The chemical structures, structure-activity relationship, and mechanisms of action are also discussed.
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; HIV Infections; Humans; Indoles; Structure-Activity Relationship
PubMed: 34636313
DOI: 10.2174/1568026621666211012111901