ABSTRACT
AIMS: To predict potential drugs for COVID-19 by using molecular docking for virtual screening of drugs approved for other clinical applications. BACKGROUND: SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by the WHO due to high mortality, high basic reproduction number, and lack of clinically approved drugs and vaccines. The genome of the virus responsible for COVID-19 has been sequenced. In addition, the three-dimensional structure of the main protease has been determined experimentally. OBJECTIVE: To identify potential drugs that can be repurposed for treatment of COVID-19 by using molecular docking based virtual screening of all approved drugs. METHODS: A list of drugs approved for clinical use was obtained from the SuperDRUG2 database. The structure of the target in the apo form, as well as structures of several target-ligand complexes, were obtained from RCSB PDB. The structure of SARS-CoV-2 Mpro determined from X-ray diffraction data was used as the target. Data regarding drugs in clinical trials for COVID-19 was obtained from clinicaltrials.org. Input for molecular docking based virtual screening was prepared by using Obabel and customized python, bash, and awk scripts. Molecular docking calculations were carried out with Vina and SMINA, and the docked conformations were analyzed and visualized with PLIP, Pymol, and Rasmol. RESULTS: Among the drugs that are being tested in clinical trials for COVID-19, Danoprevir and Darunavir were predicted to have the highest binding affinity for the Main protease (Mpro) target of SARS-CoV-2. Saquinavir and Beclabuvir were identified as the best novel candidates for COVID-19 therapy by using Virtual Screening of drugs approved for other clinical indications. CONCLUSION: Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , COVID-19/virology , Drug Evaluation, Preclinical , Molecular Docking Simulation , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Benzazepines/chemistry , Benzazepines/pharmacology , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Darunavir/chemistry , Darunavir/pharmacology , Drug Repositioning , High-Throughput Screening Assays , Humans , Indoles/chemistry , Indoles/pharmacology , Isoindoles/chemistry , Isoindoles/pharmacology , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/pharmacology , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacology , Saquinavir/chemistry , Saquinavir/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Garlic has been used as a traditional medicine to treat various diseases. Garlic reduces the risk of some diseases. This protective effect is due to the organosulfur compounds of garlic. The aim of this study was to investigate the inhibition effects of garlic-derived compounds on human immunodeficiency virus type 1 (HIV-1) and as the most important anti-HIV-1 medicine. The activation of saquinavir is believed to be the principal mechanism behind the protective effects of HIV-1. Our theoretical calculations are performed for blood phase by using the density functional theory for the main compounds of garlic. The chemical activity and solubility of ajoene and the mainly derived compounds of garlic as theoretical calculations are important for the medical research comparing with the other compounds of the garlic. The theoretical calculations have helped us to determine which active ingredient of the garlic having inhibition effects on HIV-1 and saquinavir.
Subject(s)
Anti-HIV Agents/pharmacology , Garlic/chemistry , HIV Protease Inhibitors/pharmacology , HIV Protease/metabolism , HIV-1/drug effects , Phytochemicals/pharmacology , Saquinavir/antagonists & inhibitors , Anti-HIV Agents/chemistry , Antioxidants/chemistry , Antioxidants/pharmacology , Catalytic Domain , Computational Biology , Density Functional Theory , Disulfides/chemistry , Disulfides/pharmacology , Drug Interactions , Drug Synergism , HIV Protease/chemistry , HIV Protease Inhibitors/chemistry , HIV-1/enzymology , Molecular Docking Simulation , Phytochemicals/chemistry , Saquinavir/agonists , Saquinavir/chemistry , Saquinavir/pharmacology , Solubility , SulfoxidesABSTRACT
The aim of this investigation was to develop novel oil-in-water (o/w) nanoemulsions containing Saquinavir (SQV), an anti-HIV protease inhibitor, for enhanced oral bioavailability and brain disposition. SQV was dissolved in different types of edible oils rich in essential polyunsaturated fatty acids (PUFA) to constitute the internal oil phase of the nanoemulsions. The external phase consisted of surfactants Lipoid-80 and deoxycholic acid dissolved in water. The nanoemulsions with an average oil droplet size of 100-200 nm, containing tritiated [(3)H]-SQV, were administered orally and intravenously to male Balb/c mice. The SQV bioavailability as well as distribution in different organ systems was examined. SQV concentrations in the systemic circulation administered in flax-seed oil nanoemulsions were threefold higher as compared to the control aqueous suspension. The oral bioavailability and distribution to the brain, a potential sanctuary site for HIV, were significantly enhanced with SQV delivered in nanoemulsion formulations. In comparing SQV in flax-seed oil nanoemulsion with aqueous suspension, the maximum concentration (C(max)) and the area-under-the-curve (AUC) values were found to be five- and threefold higher in the brain, respectively, suggesting enhanced rate and extent of SQV absorption following oral administration of nanoemulsions. The results of this study show that oil-in-water nanoemulsions made with PUFA-rich oils may be very promising for HIV/AIDS therapy, in particular, for reducing the viral load in important anatomical reservoir sites.
Subject(s)
Brain/metabolism , Nanotechnology/methods , Saquinavir/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Biological Availability , Deoxycholic Acid/chemistry , Emulsions , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacokinetics , Injections, Intravenous , Linseed Oil/chemistry , Male , Mice , Mice, Inbred BALB C , Microscopy, Electron, Transmission , Particle Size , Phosphatidylcholines/chemistry , Plant Oils/chemistry , Saquinavir/administration & dosage , Saquinavir/chemistry , Sonication , Static Electricity , Sunflower Oil , Surface PropertiesABSTRACT
AIM: To report the preliminary result of the HIV inhibitor screening based on cheminformatics tools and the traditional Chinese medicine database. METHODS: Database search was carried out with saquinavir molecule as a template, further screening was made with docking. Detailed studies using molecular dynamics simulation of 50 ps and 200 ps were made with respect to a potential leading compound, leucovorin. RESULTS: The leucovorin molecule distinguished from other molecules as a potential drug candidate and is subject to extensive studies. The bonding profile and energy were calculated with MD simulations. CONCLUSION: Our results could be very helpful when we modify leucovorin or design new inhibitors against HIV.
Subject(s)
Anti-HIV Agents/chemistry , Drug Design , HIV Protease Inhibitors/chemistry , HIV Protease/chemistry , Medicine, Chinese Traditional , Databases, Factual , Drug Evaluation, Preclinical/methods , Leucovorin/chemistry , Ligands , Models, Molecular , Molecular Conformation , Saquinavir/chemistryABSTRACT
With a view to improving the pharmacological properties, safety and pharmacokinetic profiles of current protease inhibitors, the synthesis of various acyl-substituted saquinavir and indinavir prodrugs, their in vitro stability with respect to hydrolysis and their anti-HIV (LAI and HTLV IIIB) activity and cytotoxicity in CEM-SS and MT4 cells have been investigated. Hydrolysis of the ester bond and liberation of the active free drug was found to be crucial for HIV inhibition: the faster the hydrolysis, the closer the anti-HIV activity was to that of the respective parent drug. This is the case for most of the C-14-substituted indinavir and saquinavir derivatives (IC50 from 10 to 360 nM for ester half-lives of 90 min to 40 h). Concomitantly, the level of HIV inhibition is very low for the prodrugs for which hydrolysis is very slow. This is the case with the myristoyl or oleyl saquinavir esters, owing to the stable masking of the hydroxyl that is part of the peptidomimetic non-cleavable transition state isostere responsible for the inhibitory potency of saquinavir (and indinavir). In contrast, the anti-HIV activity of the monosubstituted C-8 indinavir prodrugs seems not to be correlated with their resistance to hydrolysis, as expected (the C-8 hydroxyl of indinavir is not involved in the transition state isostere). No cytotoxicity was detected for the indinavir and saquinavir prodrugs for concentrations as high as 10 or even 100 microM, thus indicating promising therapeutic potential.