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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 -
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 -
Journal of Biomolecular Structure &... Jun 2021SARS-CoV-2 is a new generation of coronavirus, which was first determined in Wuhan, China, in December 2019. So far, however, there no effective treatment has been found...
SARS-CoV-2 is a new generation of coronavirus, which was first determined in Wuhan, China, in December 2019. So far, however, there no effective treatment has been found to stop this new generation of coronavirus but discovering of the crystal structure of SARS-CoV-2 main protease (SARS-CoV-2 Mpro) may facilitate searching for new therapies for SARS-COV-2. The aim was to assess the effectiveness of available FDA approved drugs which can construct a covalent bond with Cys145 inside binding site SARS-CoV-2 main protease by using covalent docking screening. We conducted the covdock module MMGBSA module in the Schrodinger suite 2020-1, to examine the covalent bonding utilizing. Besides, we submitted the top three drugs to molecular dynamics simulations via Gromacs 2018.1. The covalent docking showed that saquinavir, ritonavir, remdesivir, delavirdine, cefuroxime axetil, oseltamivir and prevacid have the highest binding energies MMGBSA of -72.17, -72.02, -65.19, -57.65, -54.25, -51.8, and -51.14 kcal/mol, respectively. The 50 ns molecular dynamics simulation was conducted for saquinavir, ritonavir and remdesivir to evaluate the stability of these drugs inside the binding pocket of SARS-CoV-2 main protease. The current study provides a powerful in silico results, means for rapid screening of drugs as anti-protease medications and recommend that the above-mentioned drugs can be used in the treatment of SARS-CoV-2 in combined or sole therapy.Communicated by Ramaswamy H. Sarma.
Topics: COVID-19; Humans; Molecular Docking Simulation; Protease Inhibitors; SARS-CoV-2; Viral Nonstructural Proteins
PubMed: 32364041
DOI: 10.1080/07391102.2020.1764392 -
Journal of Biomolecular Structure &... Aug 2020AIDS is a global infection involving several complications and its increasing prevalence every year has prioritized our study. Therapy associated with HIV has led to...
AIDS is a global infection involving several complications and its increasing prevalence every year has prioritized our study. Therapy associated with HIV has led to emergence of multidrug resistance and toxicity. Thus, the development of a potent, affordable and safe anti-HIV drug is a global concern. Among the different targets developed, inhibition of non-nucleoside reverse transcriptase (NNRT) is found to be effective and promising. Etravirine, efavirenz, nevirapine, rilpivirine and delavirdine are the marketed NNRTIs available. This study is focused on computational prediction of hit molecules as well as repurposing of various FDA-approved drugs as potential NNRTIs. A synthetic database from ZINCpharmer, publicly available natural databases of coumarins, chromones and chalcones, and two databases of FDA-approved drugs for repurposing were screened to check for the possibility of these compounds to possess anti-HIV activity. Study utilizes a structure-based approach with the generated pharmacophore of target protein (PDB ID: 3MEC), screening of selected datasets is carried out using the Phase tool of Schrodinger. The top filtered compounds with good fitness score were proceeded to molecular docking studies to study their binding affinity to the target. Energy-based calculations using Prime MM-GBSA of Schrodinger was performed to determine free binding energy of the complexes. Prediction of pharmacokinetic parameters of top compounds is further carried out and reported. All the results obtained from different databases are compiled, interpreted and five molecules were subjected to molecular dynamic studies to further confirm the prediction and identified hit molecules for screening as potential NNRTIs.Communicated by Ramaswamy H. Sarma.
Topics: Anti-HIV Agents; Drug Repositioning; HIV Infections; HIV Reverse Transcriptase; Humans; Molecular Docking Simulation; Reverse Transcriptase Inhibitors
PubMed: 31526232
DOI: 10.1080/07391102.2019.1663263 -
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