Discovery of novel inhibitors against main protease (Mpro) of SARS-CoV-2 via virtual screening and biochemical evaluation.
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ABSTRACT:
SUBMITTER: Guo S
PROVIDER: S-EPMC7903152 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) pandemic represents a global challenge. SARS-CoV-2's ability to replicate in host cells relies on the action of its non-structural proteins, like its main protease (Mpro). This cysteine protease acts by processing the viruses' precursor polyproteins. As proteases, together with polymerases, are main targets of antiviral drug design, we here have performed biochemical high throughput screening (HTS) with recombinantly expressed SARS-CoV-2 Mpro. A fluorescent assay was used to identify inhibitors in a compound library containing known drugs, bioactive molecules and natural products. These screens led to the identification of 13 inhibitors with IC50 values ranging from 0.2 μM to 23 μM. The screens confirmed several known SARS-CoV Mpro inhibitors as inhibitors of SARS-CoV-2 Mpro, such as the organo-mercuric compounds thimerosal and phenylmercuric acetate. Benzophenone derivatives could also be identified among the most potent screening hits. Additionally, Evans blue, a sulfonic acid-containing dye, could be identified as an Mpro inhibitor. The obtained compounds could be of interest as lead compounds for the development of future SARS-CoV-2 drugs.
| S-EPMC7537881 | biostudies-literature
Project description:SARS-CoV-2 is a highly hazardous species that can infect people with Covid-19 disease, dramatically increasing mortality rates worldwide. Plenty of researches have been done to find drugs or inhibitors, with this study aiming to identify an inhibitor within the ChEMBL database using computational approaches. From the ChEMBL library, 19,43,048 compounds which are known type of small compounds and proteins were downloaded and docked with the Main protease (Mpro). After performing compound screening using Lipinski's rule, Qikprop analysis following with virtual Screening, Induced Fit Docking (IFD) and MM-GBSA analysis with the Glide and Prime modules of Schrödinger, the best complex was subjected to MD simulation with Desmond. According to the docking results, small protein 2,371,668 and compound 1,090,395 were docked with Main protease with -12.6, -12.0 kcal/mol dock score and interacted with the functional site residues His 41 and Cys 145, as well as the binding site residues Thr 26, Phe 140, Asn 142, Gly 143, Glu 166, and Gln 189. Complex structures were shown to be steadier by the MD simulation study because both the ligands heavy atoms and the protein Cα atoms' RMSD values fell within acceptable ranges. As a result, this research suggests that the molecule CHEMBL2371668 and the compound CHEMBL1090395 may inhibit the activity of Main protease, and the usefulness of these molecules will be examined further through experimental research.
| S-EPMC10663854 | biostudies-literature
Project description:During almost all 2020, coronavirus disease 2019 (COVID-19) pandemic has constituted the major risk for the worldwide health and economy, propelling unprecedented efforts to discover drugs for its prevention and cure. At the end of the year, these efforts have culminated with the approval of vaccines by the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA) giving new hope for the future. On the other hand, clinical data underscore the urgent need for effective drugs to treat COVID-19 patients. In this work, we embarked on a virtual screening campaign against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mpro chymotrypsin-like cysteine protease employing our in-house database of peptide and non-peptide ligands characterized by different types of warheads acting as Michael acceptors. To this end, we employed the AutoDock4 docking software customized to predict the formation of a covalent adduct with the target protein. In vitro verification of the inhibition properties of the most promising candidates allowed us to identify two new lead inhibitors that will deserve further optimization. From the computational point of view, this work demonstrates the predictive power of AutoDock4 and suggests its application for the in silico screening of large chemical libraries of potential covalent binders against the SARS-CoV-2 Mpro enzyme.
| S-EPMC8029447 | biostudies-literature
Project description:The global emergency caused by COVID-19 makes the discovery of drugs capable of inhibiting SARS-CoV-2 a priority, to reduce the mortality and morbidity of this disease. Repurposing approved drugs can provide therapeutic alternatives that promise rapid and ample coverage because they have a documented safety record, as well as infrastructure for large-scale production. The main protease of SARS-CoV-2 (Mpro) is an excellent therapeutic target because it is critical for viral replication; however, Mpro has a highly flexible active site that must be considered when performing computer-assisted drug discovery. In this work, potential inhibitors of the main protease (Mpro) of SARS-Cov-2 were identified through a docking-assisted virtual screening procedure. A total of 4384 drugs, all approved for human use, were screened against three conformers of Mpro. The ligands were further studied through molecular dynamics simulations and binding free energy analysis. A total of nine currently approved molecules are proposed as potential inhibitors of SARS-CoV-2. These molecules can be further tested to speed the development of therapeutics against COVID-19.
| S-EPMC7316061 | biostudies-literature
Project description:Global health is under heavy threat by a worldwide pandemic caused by a new type of coronavirus (COVID-19) since its rapid spread in China in 2019 [1]. Currently, there are no approved specific drugs and effective treatment for COVID-19 infection, but several available drugs are known to facilitate tentative treatment. Since drug design, development and testing procedures are time-consuming [2], [1], [2], [3], virtual screening studies with the aid of available drug databases take the initiative at this point and save the time. Besides, drug repurposing strategies promises to identify new agents for the novel diseases in a time-critical fashion. In this study, we used structure based virtual screening method on FDA approved drugs and compounds in clinical trials. As a result of this study we choose three most prominent compounds for further studies. Here we show that these three compounds (dobutamine and its two derivatives) can be considered as promising inhibitors for SARS-CoV-2 main protease and results also demonstrate the possible interactions of dobutamine and its derivatives with SARS-CoV-2 main protease (6W63) [6]. Our efforts in this work directly address current urgency of a new drug discovery against COVID-19.
| S-EPMC7550866 | biostudies-literature
Project description:The main protease (Mpro) of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings using a library of microbial natural products (>24,000 compounds). Subsequent filtering of the resulted hits according to the Lipinski's rules was applied to select only the drug-like molecules. Top-scoring hits were further filtered out depending on their ability to show constant good binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme's conformers. Final MDS experiments were performed on the ligand-protein complexes (compounds 1-12, Table S1) to verify their binding modes and calculate their binding free energy. Consequently, a final selection of six compounds (1-6) was proposed to possess high potential as anti-SARS-CoV-2 drug candidates. Our study provides insight into the role of the Mpro structural flexibility during interactions with the possible inhibitors and sheds light on the structure-based design of anti-coronavirus disease 2019 (COVID-19) therapeutics targeting SARS-CoV-2.
| S-EPMC7409236 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of the most devastating pandemics of recent times. The lack of potent novel antivirals had led to global health crises; however, emergence and approval of potent inhibitors of the viral main protease (Mpro), such as Pfizer's newly approved nirmatrelvir, offers hope not only in the therapeutic front but also in the context of prophylaxis against the infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, and lessons learnt from previous and currently ongoing pandemics have taught us that these viruses can easily escape selection pressure through mutation of vital target amino acid residues in monotherapeutic settings. In this paper, we review nirmatrelvir and its binding to SARS-CoV-2 Mpro and draw a comparison to inhibitors of HIV protease that were rendered obsolete by emergence of resistance mutations, emphasizing potential pitfalls in the design of inhibitors that may be of important relevance to the long-term use of novel inhibitors against SARS-CoV-2.
| S-EPMC8998604 | biostudies-literature
Project description:Background: Due to the constant mutation of virus and the lack of specific therapeutic drugs, the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still poses a huge threat to the health of people, especially those with underlying diseases. Therefore, drug discovery against the SARS-CoV-2 remains of great significance. Methods: With the main protease of virus as the inhibitor target, 9,614 genistein derivatives were virtually screened by LeDock and AutoDock Vina, and the top 20 compounds with highest normalized scores were obtained. Molecular dynamics simulations were carried out for studying interactions between these 20 compounds and the target protein. The drug-like properties, activity, and ADMET of these compounds were also evaluated by DruLiTo software or online server. Results: Twenty compounds, including compound 11, were screened by normalized molecular docking, which could bind to the target through multiple non-bonding interactions. Molecular dynamics simulation results showed that compounds 2, 4, 5, 11, 13, 14, 17, and 18 had the best binding force with the target protein of SARS-CoV-2, and the absolute values of binding free energies all exceeded 50 kJ/mol. The drug-likeness properties indicated that a variety of compounds including compound 11 were worthy of further study. The results of bioactivity score prediction found that compounds 11 and 12 had high inhibitory activities against protease, which indicated that these two compounds had the potential to be further developed as COVID-19 inhibitors. Finally, compound 11 showed excellent predictive ADMET properties including high absorption and low toxicity. Conclusion: These in silico work results show that the preferred compound 11 (ZINC000111282222), which exhibited strong binding to SARS-CoV-2 main protease, acceptable drug-like properties, protease inhibitory activity and ADMET properties, has great promise for further research as a potential therapeutic agent against COVID-19.
| S-EPMC9452787 | biostudies-literature
Project description:The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.
| S-EPMC8491550 | biostudies-literature
Project description:Corona Virus Disease 2019 (COVID-19), referred to as 'New Coronary Pneumonia', is a type of acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Mpro is one of the main targets for treating COVID-19. The current research on Mpro mainly focuses on the repurposing of old drugs, and there are only a few novel ligands that inhibit Mpro. In this research, we used computational free energy calculation to screen a compound library against Mpro, and discovered four novel compounds with the two best compounds (AG-690/13507628 and AG-690/13507724) having experimental measured IC50 of just under 3 μM and low cell toxicity. Detailed decomposition of the interactions between the inhibitors and Mpro reveals key interacting residues and interactions that determine the activity. The results from this study should provide a basis for further development of anti-SARS-CoV-2 drugs.Communicated by Ramaswamy H. Sarma.
| S-EPMC8436407 | biostudies-literature