Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(20), С. 12235 - 12235

Опубликована: Окт. 13, 2022

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated highest binding affinities towards Mpro. A dynamics study at 200 ns was also carried out for most promising anticoagulants to provide insights into dynamic thermodynamic properties compounds. Moreover, a quantum mechanical conducted which helped us attest some findings. biological evaluation (in vitro) compounds performed by carrying MTT cytotoxicity assay crystal violet order assess inhibitory concentration 50 (IC50). It is worth noting that displayed intrinsic potential inhibition with an IC50 value 5.60 µM safety index 25.33. addition, fondaparinux sodium dabigatran showed activities values 8.60 9.40 µM, respectively, indexes 17.60 15.10, respectively. Mpro enzyme investigated utilizing tipranavir as reference standard. Interestingly, attained 2.36 surpassing (IC50 = 7.38 µM) more than three-fold. Furthermore, highly eligible 10.59 µM. Finally, SAR discussed, counting on findings both vitro approaches.

Язык: Английский

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Ligand-based design, synthesis, computational insights, andin vitrostudies of novelN-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 2112 - 2132

Опубликована: Июль 31, 2022

The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development new effective therapeutic interventions for battle against SARS-CoV-2. A series

Язык: Английский

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Investigating the possible mechanisms of pirfenidone to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2

Life Sciences, Год журнала: 2022, Номер 309, С. 121048 - 121048

Опубликована: Окт. 7, 2022

Язык: Английский

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Lessons we learned during the past four challenging years in the COVID-19 era: pharmacotherapy, long COVID complications, and vaccine development

Virology Journal, Год журнала: 2024, Номер 21(1)

Опубликована: Апрель 26, 2024

About four years have passed since the detection of first cases COVID-19 in China. During this lethal pandemic, millions people lost their lives around world. Since waves infection, various pharmacotherapeutic agents been examined management COVID-19. Despite all these efforts pharmacotherapy, drug repurposing, and design development new drugs, multiple organ involvement complications occurred during Some became chronic long-lasting which led to "long COVID" syndrome appearance. Therefore, best way eradicate pandemic is prophylaxis through mass vaccination. In regard, vaccine platforms including inactivated vaccines, nucleic acid-based vaccines (mRNA DNA vaccines), adenovirus-vectored protein-based subunit designed developed prevent or reduce hospitalization, mortality rates. focused review, at first, most commonly reported clinical presentations summarized. addition, different therapeutic regimens latest status listed. Furthermore, related signs, symptoms, mentioned. At end, effectiveness available with against early SARS-CoV-2 variants currently circulating interest (VOI) necessity booster shots summarized discussed more detail.

Язык: Английский

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Design and statistical optimisation of emulsomal nanoparticles for improved anti-SARS-CoV-2 activity of N -(5-nitrothiazol-2-yl)-carboxamido candidates: in vitro and in silico studies

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2023, Номер 38(1)

Опубликована: Апрель 24, 2023

In this article, emulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g) in an attempt improve their biological availability and antiviral activity. Next, both cytotoxicity anti-SARS-CoV-2 activities of examined compounds loaded EMLs (F3a-g) assessed Vero E6 cells via MTT assay calculate CC50 inhibitory concentration 50 (IC50) values. The most potent 3e-loaded (F3e) elicited a selectivity index 18 with IC50 value 0.73 μg/mL. Moreover, F3e was selected for further elucidation possible mode action where results showed that it exhibited combination virucidal (>90%), viral adsorption (>80%), replication (>60%) inhibition. Besides, molecular docking MD simulations towards SARS-CoV-2 Mpro performed. Finally, structure-activity relationship (SAR) study focussed on studying influence altering size, type, flexibility α-substituent carboxamide addition compound contraction activity.HighlightsEmulsomes (3a-3g).The μg/mL against SARS-CoV-2.F3e inhibition.Molecular docking, dynamics (MD) simulations, MM-GBSA calculations performed.Structure-activity discussed

Язык: Английский

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Lipid-encapsulated gold nanoparticles: an advanced strategy for attenuating the inflammatory response in SARS-CoV-2 infection

Journal of Nanobiotechnology, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 15, 2025

Nanodrugs play a crucial role in biomedical applications by enhancing drug delivery. To address safety and toxicity concerns associated with nanoparticles, lipid-nanocarrier-based delivery systems have emerged as promising approach for developing next-generation smart nanomedicines. Ginseng has traditionally been used various therapeutic purposes, including antiviral activity. This study aimed to prepare biocompatible therapeutically potent Korean ginseng nanoemulsion (KGS-NE) using seed oil (GSO), optimize its encapsulation efficiency, evaluate Various techniques were utilized confirm the KGS-NE formation. Energy-dispersive X-ray spectroscopy identified gold nanoparticles highest Au peak at 2.1 keV. Selected area diffraction patterns revealed crystallographic structures. FT-IR spectrometry detected functional groups, peaks 2922.09 cm−1 (alkene C–H stretching), 1740.24 (aldehyde C=O 1098.07 (C–O stretching secondary alcohol). Storage stability studies showed that maintained size 6 months 4 °C. The exhibited dose-dependent suppression of HCoV-OC43 viral replication Vero E6 cells. RNA sequencing analysis unveiled differentially expressed genes (DEGs) specifically involved ABC transporters signaling pathway. oral administration facilitated recovery mice induced receptor binding domain (RBD) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, confirmed inflammatory markers expression lung tissue. In Syrian hamster infected SARS-CoV-2 model, lungs dissected enlarged morphology cytokines. effect was mitigated administration, observed through H&E qRT-PCR analysis. Biochemical concentrations demonstrated had no adverse effects on kidney liver. Our findings strongly suggest administering models potential effectively mitigate inflammation against coronavirus. indicates new strategy nano-agent SARS-CoV-2.

Язык: Английский

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Recent advances in small-molecular therapeutics for COVID-19

Precision Clinical Medicine, Год журнала: 2022, Номер 5(4)

Опубликована: Сен. 24, 2022

Abstract The COVID-19 pandemic poses a fundamental challenge to global health. Since the outbreak of SARS-CoV-2, great efforts have been made identify antiviral strategies and develop therapeutic drugs combat disease. There are different for developing small molecular anti-SARS-CoV-2 drugs, including targeting coronavirus structural proteins (e.g. spike protein), non-structural (nsp) RdRp, Mpro, PLpro, helicase, nsp14, nsp16), host proteases TMPRSS2, cathepsin, furin) pivotal mediating endocytosis PIKfyve), as well endosome acidification agents immune response modulators. Favipiravir chloroquine that were identified earlier in this epidemic repurposed clinical therapy based on these strategies. However, their efficacies controversial. Currently, three agents, remdesivir, molnupiravir, Paxlovid (PF-07321332 plus ritonavir), granted emergency use authorization or approved many countries due significant curative effects phase III trials. Meanwhile, large number promising drug candidates entered evaluation. development brings hope us finally conquer COVID-19. In account, we conducted comprehensive review recent advances molecule according target classification. Here present all most important each target, discuss challenges perspectives future research drugs.

Язык: Английский

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Evaluation of the mutagenic effects of Molnupiravir and N4‐hydroxycytidine in bacterial and mammalian cells by HiFi sequencing

Environmental and Molecular Mutagenesis, Год журнала: 2022, Номер 63(7), С. 320 - 328

Опубликована: Авг. 1, 2022

Abstract Molnupiravir (MOV) is used to treat COVID‐19. In cells, MOV converted the ribonucleoside analog N4‐hydroxycytidine (NHC) and incorporated into SARS‐CoV‐2 RNA genome during its replication, resulting in mutations. The widespread accumulation of such mutations inhibits propagation. Although safety assessments by many regulatory agencies across world have concluded that genotoxic risks associated with clinical use are low, concerns remain it could induce DNA patients, particularly because numerous vitro studies shown NHC a mutagen. this study, we HiFi sequencing, technique can detect ultralow‐frequency substitution whole genomes, evaluate mutagenic effects E. coli mouse lymphoma L5178Y cells human lymphoblastoid TK6 cells. all models, exposure these compounds increased genome‐wide mutation frequencies dose‐dependent manner, increases were mainly composed A:T → G:C transitions. concentrations for mammalian comparable those observed plasma humans who received doses MOV.

Язык: Английский

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Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2

Molecules, Год журнала: 2023, Номер 28(18), С. 6603 - 6603

Опубликована: Сен. 13, 2023

The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. disease quickly spreads due the highly infectious SARS-CoV-2 virus, which undergone numerous mutations. Despite intense research efforts by scientific community since its emergence 2019, no effective therapeutics have been discovered yet. While some repurposed drugs used control global outbreak save lives, none proven universally effective, particularly for severely infected patients. Although spread of is generally under control, anti-SARS-CoV-2 agents are still needed combat current future infections. This study reviews most promising containing indolyl heterocycle, an essential scaffold many alkaloids with diverse bio-properties various biological fields. also discusses natural synthetic indole-containing compounds properties computer-aided drug design (in silico studies) optimizing hits/leads.

Язык: Английский

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Machine learning coupled with causal inference to identify COVID-19 related chemicals that pose a high concern to drinking water

iScience, Год журнала: 2024, Номер 27(2), С. 109012 - 109012

Опубликована: Янв. 25, 2024

Various synthetic substances were utilized in large quantities during the recent coronavirus pandemic, COVID-19. Some of these chemicals could potentially enter drinking water sources. Persistent, mobile, and toxic (PMT) have been recognized as a threat to resources. It has not yet assessed how many COVID-19 related be considered PMT substances. One reason is lack high-quality experimental data for identification To solve this problem, we applied machine learning model identify among chemicals. The optimal achieved an accuracy 90.6% based on external test data. interpretation causal inference indicated that our approach understood causation between properties molecular descriptors. Notably, screening results showed over 60% are candidate substances, which should prioritized prevent undue pollution

Язык: Английский

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