Structure-Based Virtual Screening of a Natural Product Database to Identify Several Possible SARS-CoV-2 Main Protease Inhibitors

Singam, Azhagiya; Ramaprasad, Ettayapuram; Michele,; merrill, La; Kathleen, A. Mahon; Durkin,; Martyn, T; Smith, Stacy

doi:10.26434/chemrxiv.12143394.v1

Cited by 4 publications

(5 citation statements)

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“…In silico analysis regarded schaftoside as one of the top 10 among 318 phytochemicals that had significantly lower binding energy to Mpro (the main protease of SARSCoV-2) and ACE2 (angiotensin-converting enzyme 2) as compared to the reference molecule PRD_002214 (Joshi et al 2020 ). Molecular docking indicated carlinoside was the top candidate against Mpro (Ettayapuram Ramaprasad et al 2020 ; Joshi et al 2020 ). Therefore, flavone C -arabinosides are expected to be a powerful weapon for potential treatment of SARSCoV-2.…”

Section: Introductionmentioning

confidence: 99%

De novo biosynthesis of C-arabinosylated flavones by utilization of indica rice C-glycosyltransferases

Chen

Sun

Wang

et al. 2021

Bioresour. Bioprocess.

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Flavone C-arabinosides/xylosides are plant-originated glycoconjugates with various bioactivities. However, the potential utility of these molecules is hindered by their low abundance in nature. Engineering biosynthesis pathway in heterologous bacterial chassis provides a sustainable source of these C-glycosides. We previously reported bifunctional C-glucosyl/C-arabinosyltransferases in Oryza sativa japonica and O. sativa indica, which influence the C-glycoside spectrum in different rice varieties. In this study, we proved the C-arabinosyl-transferring activity of rice C-glycosyltransferases (CGTs) on the mono-C-glucoside substrate nothofagin, followed by taking advantage of specific CGTs and introducing heterologous UDP-pentose supply, to realize the production of eight different C-arabinosides/xylosides in recombinant E. coli. Fed-batch fermentation and precursor supplement maximized the titer of rice-originated C-arabinosides to 20–110 mg/L in an E. coli chassis. The optimized final titer of schaftoside and apigenin di-C-arabinoside reached 19.87 and 113.16 mg/L, respectively. We demonstrate here the success of de novo bio-production of C-arabinosylated and C-xylosylated flavones by heterologous pathway reconstitution. These results lay a foundation for further optimal manufacture of complex flavonoid compounds in microbial cell factories.

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Section: Introductionmentioning

confidence: 99%

De novo biosynthesis of C-arabinosylated flavones by utilization of indica rice C-glycosyltransferases

Chen

Sun

Wang

et al. 2021

Bioresour. Bioprocess.

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“…The trial compounds included in this study are Remdesivir, Chloroquine, Lopinavir, Oseltamivir, Ritonavir, Favipiravir, Baricitinib, Darunavir and Umifenovir [34][35][36] . We also would like to recall that many researchers have screened compounds from different chemical-spaces such as natural products database 37 , FDA-approved compounds 38 , phytochemicals [39][40][41] , marine natural products 42 ChEMBL [43][44][45] and pubchem 44 databases against different viral targets by using different scoring functions 46 . The main difference of the current study is that we have considered four different viral targets and so we are able to propose drug cocktails effective for Covid-19 along with suggestions of drugs which have the potential as multi-targeting drugs.…”

mentioning

confidence: 99%

Searching for target-specific and multi-targeting organics for Covid-19 in the Drugbank database with a double scoring approach

Murugan

Kumar

Jeyakanthan

et al. 2020

Sci Rep

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The current outbreak of Covid-19 infection due to SARS-CoV-2, a virus from the coronavirus family, has become a major threat to human healthcare. The virus has already infected more than 44 M people and the number of deaths reported has reached more than 1.1 M which may be attributed to lack of medicine. The traditional drug discovery approach involves many years of rigorous research and development and demands for a huge investment which cannot be adopted for the ongoing pandemic infection. Rather we need a swift and cost-effective approach to inhibit and control the viral infection. With the help of computational screening approaches and by choosing appropriate chemical space, it is possible to identify lead drug-like compounds for Covid-19. In this study, we have used the Drugbank database to screen compounds against the most important viral targets namely 3C-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp) and the spike (S) protein. These targets play a major role in the replication/transcription and host cell recognition, therefore, are vital for the viral reproduction and spread of infection. As the structure based computational screening approaches are more reliable, we used the crystal structures for 3C-like main protease and spike protein. For the remaining targets, we used the structures based on homology modeling. Further, we employed two scoring methods based on binding free energies implemented in AutoDock Vina and molecular mechanics—generalized Born surface area approach. Based on these results, we propose drug cocktails active against the three viral targets namely 3CLpro, PLpro and RdRp. Interestingly, one of the identified compounds in this study i.e. Baloxavir marboxil has been under clinical trial for the treatment of Covid-19 infection. In addition, we have identified a few compounds such as Phthalocyanine, Tadalafil, Lonafarnib, Nilotinib, Dihydroergotamine, R-428 which can bind to all three targets simultaneously and can serve as multi-targeting drugs. Our study also included calculation of binding energies for various compounds currently under drug trials. Among these compounds, it is found that Remdesivir binds to targets, 3CLpro and RdRp with high binding affinity. Moreover, Baricitinib and Umifenovir were found to have superior target-specific binding while Darunavir is found to be a potential multi-targeting drug. As far as we know this is the first study where the compounds from the Drugbank database are screened against four vital targets of SARS-CoV-2 and illustrates that the computational screening using a double scoring approach can yield potential drug-like compounds against Covid-19 infection.

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“…Unlike the previous compound, in this case the molecule stretches completely along the groove that goes from S1 I to S4 ( Figure 5). Starting from S1 I , the glycoside group forms four hydrogen bonds with T 24 (3.47 Å), T 45 (2.91 Å), and S 46 (2.87 and 2.99 Å). The phenolic OH of the benzopyran ring forms an h-bond with T 26 (1.97 and 2.03 Å), while the carbonyl group forms a hydrogen bond with G 143 (3.69 Å).…”

Section: Resultsmentioning

confidence: 99%

“…In recent months, many research groups have made use of virtual screening and molecular docking techniques for the repurposing of libraries containing approved compounds [19][20][21][22], natural compounds [23][24][25][26], on-line databases [27][28][29][30], and in-house compound libraries [31].…”

Section: Introductionmentioning

confidence: 99%

Putative SARS-CoV-2 Mpro Inhibitors from an In-House Library of Natural and Nature-Inspired Products: A Virtual Screening and Molecular Docking Study

et al. 2020

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A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been the cause of a recent global pandemic. The highly contagious nature of this life-threatening virus makes it imperative to find therapies to counteract its diffusion. The main protease (Mpro) of SARS-CoV-2 is a promising drug target due to its indispensable role in viral replication inside the host. Using a combined two-steps approach of virtual screening and molecular docking techniques, we have screened an in-house collection of small molecules, mainly composed of natural and nature-inspired compounds. The molecules were selected with high structural diversity to cover a wide range of chemical space into the enzyme pockets. Virtual screening experiments were performed using the blind docking mode of the AutoDock Vina software. Virtual screening allowed the selection of structurally heterogeneous compounds capable of interacting effectively with the enzymatic site of SARS-CoV-2 Mpro. The compounds showing the best interaction with the protein were re-scored by molecular docking as implemented in AutoDock, while the stability of the complexes was tested by molecular dynamics. The most promising candidates revealed a good ability to fit into the protein binding pocket and to reach the catalytic dyad. There is a high probability that at least one of the selected scaffolds could be promising for further research

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Structure-Based Virtual Screening of a Natural Product Database to Identify Several Possible SARS-CoV-2 Main Protease Inhibitors

Cited by 4 publications

References 50 publications

De novo biosynthesis of C-arabinosylated flavones by utilization of indica rice C-glycosyltransferases

De novo biosynthesis of C-arabinosylated flavones by utilization of indica rice C-glycosyltransferases

Searching for target-specific and multi-targeting organics for Covid-19 in the Drugbank database with a double scoring approach

Putative SARS-CoV-2 Mpro Inhibitors from an In-House Library of Natural and Nature-Inspired Products: A Virtual Screening and Molecular Docking Study

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