In silico prediction of SARS-CoV-2 main protease and polymerase inhibitors: 3D-Pharmacophore modelling

Potent and biostable inhibitors of the main protease of SARS-CoV-2

CORDITE: The Curated CORona Drug InTERactions Database for SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is caused by a novel strain of coronavirus, designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has caused a global pandemic rapidly s...

Structural Basis of SARS-CoV-2 Polymerase Inhibition by Favipiravir

Pathogenesis of SARS-CoV-2 induced cardiac injury from the perspective of the virus

Background: The outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) resulted in a widespread pandemic. Various approaches involved the repositioning of antiviral remedies and other medications. Several therapies, including oral antiviral treatments, represent some approaches to adapting to the long existence of the COVID-19 pandemic. In silico studies provide valuable insights throughout drug discovery and development in compliance with global efforts to overcome the pandemic. The main protease is an essential target in the viral cycle. Computer-aided drug design accelerates the identification of potential treatments, including oral therapy. Aims: This work aims to identify potential SARS-CoV-2 main protease inhibitors using different aspects of in silico approaches. Methods: In this work, we conducted a hierarchical virtual screening of SARS-CoV-2 main protease inhibitors. A similarity search was conducted to screen molecules similar to the inhibitor PF-07321332. Concurrently, structure-based pharmacophores, besides ligand-based pharmacophores, were derived. A drug-likeness filter filtered the compounds retrieved from similarity search and pharmacophore modeling before being subjected to molecular docking. The candidate molecules that showed higher affinity to the main protease than the reference inhibitor were further filtered by absorption, distribution, metabolism, and excretion (ADME) parameters. Results: According to binding affinity and ADME analysis, four molecules (CHEMBL218022, PubChem163362029, PubChem166149100, and PubChem 162396459) were prioritized as promising hits. The compounds above were not reported before; no previous experimental studies and bioactive assays are available. Conclusion: Our time-saving approach represents a strategy for discovering novel SARS-CoV- 2 main protease inhibitors. The ultimate hits may be nominated as leads in discovering novel SARS-CoV-2 main protease inhibitors.

The outbreak of coronavirus disease 2019 (COVID-19) at the end of 2019 affected global health. Its infection agent was called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Wearing a mask, maintaining social distance, and vaccination are effective ways to prevent infection of SARS-CoV-2, but none of them help infected people. Targeting the enzymes of SARS-CoV-2 is an effective way to stop the replication of the virus in infected people and treat COVID-19 patients. SARS-CoV-2 main protease is a therapeutic target which the inhibition of its enzymatic activity prevents from the replication of SARS-CoV-2. A large database of molecules has been searched to identify new inhibitors for SARS-CoV-2 main protease enzyme. At the first step, ligand screening based on similarity search was used to select similar compounds to known SARS-CoV-2 main protease inhibitors. Then molecules with better predicted pharmacokinetic properties were selected. Structure-based virtual screening based on the application of molecular docking and molecular dynamics simulation methods was used to select more effective inhibitors among selected molecules in previous step. Finally two compounds were considered as SARS-CoV-2 main protease inhibitors.

Rutin and flavone analogs as prospective SARS-CoV-2 main protease inhibitors: In silico drug discovery study

Efficacy of antivirals and mRNA vaccination against an XBF clinical isolate

Mushroom-derived bioactive compounds potentially serve as the inhibitors of SARS-CoV-2 main protease: An in silico approach

Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) main protease (MPro) is recognized as an important therapeutic target protein in the drug development for COVID-19. To date, clinical trials of many vaccine and other viral protease inhibitors (PI) are currently under investigation. Undoubtedly, there are chances of possible side effects and ineffectiveness. Thus, the search for natural bio-active molecules is of great interest that will exert antiviral activity as well as have least chances of toxicity. Fungi are considered as bio-enriched source of producing antiviral compounds. This study is focused on identifying potential fungal derived antiviral molecules with good binding affinity against SARS-CoV-2 MProusing molecular docking. Semicochliodinol B was identified as the best lead molecule with higher binding affinity ([Formula: see text][Formula: see text]kcal/mol) as compared to the co-crystalized ligand ([Formula: see text][Formula: see text]kcal/mol). The results of molecular docking confirm the hydrogen bond interaction of Semicochliodinol B with Glu166 and Asn142 as well as hydrophobic interactions with 20 amino acid residues of SARS-CoV-2 MPro. Semicochliodinol B also exhibited good binding affinity against SARS-CoV MProand Middle east respiratory syndrome-related corona virus (MERS-CoV MPro), suggesting its broad-spectrum activity. Druglikeness, Absorption, distribution, metabolism, excretion (ADME) and toxicity studies also directed that Semicochliodinol B may become a promising drug candidate and thus it can be further investigated as a potential inhibitor of SARS-CoV-2 MPro.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still affecting people worldwide. Despite the good degree of immunological protection achieved through vaccination, there are still severe cases that require effective antivirals. In this sense, two specific pharmaceutical preparations have been marketed already, the RdRp polymerase inhibitor molnupiravir and the main viral protease inhibitor nirmatrelvir (commercialized as Paxlovid, a combination with ritonavir). Nirmatrelvir is a peptidomimetic acting as orally available, covalent, and reversible inhibitor of SARS-CoV-2 main viral protease. The success of this compound has revitalized the search for new peptide and peptidomimetic protease inhibitors. This highlight collects some selected examples among those recently published in the field of SARS-CoV-2.

The repercussions of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are catastrophic, and the world has yet to achieve full recovery. Several inhibitors targeting SARS-CoV-2 main protease are experiencing diminished efficacy owing to resistance-inducing mutations. The current situation implies that the quest to find potent and resilient SARS-CoV-2 main protease drugs to overcome resistance must be a continuous effort. Here, multiple receptor virtual screening and molecular dynamics (MD) simulation techniques were employed to identify novel binders from an integrated small-molecule database as leads for the discovery, design, and development of antivirals immune to resistance by SARS-CoV-2 main protease. The small-molecule database was initially screened separately against five SARS-CoV-2 main protease structures with different substrate-binding site conformations using the GOLD program, after which the fitness score of a control compound was used as the cutoff to create a shortlist of potential hits in each case. Then, 21 compounds at the intersection of all five shortlists were selected as virtual screening hits. The hits were subjected to MD simulations, identifying four novel compounds capable of remaining bound to SARS-CoV-2 main protease for up to 100 ns. Analysis of the mode of binding and interactions between each of the four compounds and SARS-CoV-2 main protease revealed that the compounds fit better into the conserved subpockets of the substrate-binding site than the control and interact with important amino acid residues. Conjointly, MD simulations, binding energy, and toxicity analysis results further demonstrated that the compounds are promising leads for the discovery, design, and development of potent drugs to augment the fight against SARS-CoV-2 main protease resistance.

The global public health has been compromised since the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in late December 2019. There are no specific antiviral drugs available to combat SARS-CoV-2 infection. Besides the rapid dissemination of SARS-CoV-2, several variants have been identified with a potential epidemiologic and pathogenic variation. This fact has forced antiviral drug development strategies to stay innovative, including new drug discovery protocols, combining drugs, and establishing new drug classes. Thus, developing novel screening methods and direct-targeting viral enzymes could be an attractive strategy to combat SARS-CoV-2 infection. In this study, we designed, optimized, and validated a cell-based assay protocol for high-throughput screening (HTS) antiviral drug inhibitors against main viral protease (3CLpro). We applied the split-GFP complementation to develop GFP-split-3CLpro HTS system. The system consists of GFP-based reporters that become fluorescent upon cleavage by SARS-CoV-2 protease 3CLpro. We generated a stable GFP-split-3CLpro HTS system valid to screen large drug libraries for inhibitors to SARS-CoV-2 main protease in the bio-safety level 2 laboratory, providing real-time antiviral activity of the tested compounds. Using this assay, we identified a new class of viral protease inhibitors derived from quinazoline compounds that worth further in vitro and in vivo validation.

Since the emergence of the pandemic of the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the discovery of antiviral phytoconstituents from medicinal plants against SARS-CoV-2 has been comprehensively researched. In this study, thirty-three plants belonging to seventeen different families used traditionally in Saudi Arabia were tested in vitro for their ability to inhibit the SARS-CoV-2 main protease (MPRO). Major constituents of the bio-active extracts were isolated and tested for their inhibition potential against this enzyme; in addition, their antiviral activity against the SARS-CoV-2 Egyptian strain was assessed. Further, the thermodynamic stability of the best active compounds was studied through focused comparative insights for the active metabolites regarding ligand–target binding characteristics at the molecular level. Additionally, the obtained computational findings provided useful directions for future drug optimization and development. The results revealed that Psiadia punctulata, Aframomum melegueta, and Nigella sativa extracts showed a high percentage of inhibition of 66.4, 58.7, and 31.5%, against SARS-CoV-2 MPRO, respectively. The major isolated constituents of these plants were identified as gardenins A and B (from P. punctulata), 6-gingerol and 6-paradol (from A. melegueta), and thymoquinone (from N. sativa). These compounds are the first to be tested invitro against SARS-CoV-2 MPRO. Among the isolated compounds, only thymoquinone (THY), gardenin A (GDA), 6-gingerol (GNG), and 6-paradol (PAD) inhibited the SARS-CoV-2 MPRO enzyme with inhibition percentages of 63.21, 73.80, 65.2, and 71.8%, respectively. In vitro assessment of SARS-CoV-2 (hCoV-19/Egypt/NRC-03/2020 (accession number on GSAID: EPI_ISL_430820) revealed a strong-to-low antiviral activity of the isolated compounds. THY showed relatively high cytotoxicity and was anti-SARS-CoV-2, while PAD demonstrated a cytotoxic effect on the tested VERO cells with a selectivity index of CC50/IC50 = 1.33 and CC50/IC50 = 0.6, respectively. Moreover, GNG had moderate activity at non-cytotoxic concentrations in vitro with a selectivity index of CC50/IC50 = 101.3/43.45 = 2.3. Meanwhile, GDA showed weak activity with a selectivity index of CC50/IC50 = 246.5/83.77 = 2.9. The thermodynamic stability of top-active compounds revealed preferential stability and SARS-CoV-2 MPRO binding affinity for PAD through molecular-docking-coupled molecular dynamics simulation. The obtained results suggest the treating potential of these plants and/or their active metabolites for COVID-19. However, further in-vivo and clinical investigations are required to establish the potential preventive and treatment effectiveness of these plants and/or their bio-active compounds in COVID-19.