The<scp>AutoDock</scp>suite at 30

Goodsell, David S.; Sanner, Michel F.; Olson, Arthur J.; Forli, Stefano

doi:10.1002/pro.3934

Cited by 107 publications

(46 citation statements)

References 63 publications

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“…For each time point, cell counts were normalized with corresponding DMSO vehicle (or PBS) -treated controls. In Alamar Blue assays, the LSD value in A549, H292, H1299, and H358 are 20 Figure S1. (C,D) Caspases -9 and -3 activities in cells treated with Hiltonol alone or polyI:C alone or Hiltonol +++ or polyI:C +++ (polyI:C+anti-IL6+stattic+AG490) for 24 h showed that Hiltonol +++ caused the highest elevation in Caspases -9 and -3 activities (red boxes).…”

Section: Hiltonol +++ Suppressed Lung Cancer Cell Proliferation Throumentioning

confidence: 99%

“…To analyze the potential molecular interaction between Hiltonol and PKR/OAS, we performed in silico predictions by AutoDock [20] and showed the potential amino acid residues (red) involved ( Figure 6A-F). The binding structure of PKR (or OAS) to Hiltonol is shown in Figure 6B,E, respectively.…”

Section: In Silico Analysis Showed Interaction Between Hiltonol and Pmentioning

confidence: 99%

“…PKR (accession number: P19525.2) and OAS (accession number: P00973) were analyzed for potential Hiltonol binding sites. AutoDock (http://autodock.scripps.edu/ (accessed on 6 October 2020)) was used for RNA-binding site prediction [20]. Hiltonol structurally contains 4 molecular component units (Polyinosinic acid, Glycolic acid, Cytosine arabinoside monophosphate and (4-Aminobutyl)carbamic acid).…”

Section: Computational Prediction Of Hiltonol Binding Sites In Pkr Anmentioning

confidence: 99%

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Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment

Chang

Zhang

et al. 2021

IJMS

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NSCLC (non-small cell lung cancer) is a leading cause of cancer-related deaths worldwide. Clinical trials showed that Hiltonol, a stable dsRNA representing an advanced form of polyI:C (polyinosinic-polycytidilic acid), is an adjuvant cancer-immunomodulator. However, its mechanisms of action and effect on lung cancer have not been explored pre-clinically. Here, we examined, for the first time, how a novel Hiltonol cocktail kills NSCLC cells. By retrospective analysis of NSCLC patient tissues obtained from the tumor biobank; pre-clinical studies with Hiltonol alone or Hiltonol+++ cocktail [Hiltonol+anti-IL6+AG490 (JAK2 inhibitor)+Stattic (STAT3 inhibitor)]; cytokine analysis; gene knockdown and gain/loss-of-function studies, we uncovered the mechanisms of action of Hiltonol+++. We demonstrated that Hiltonol+++ kills the cancer cells and suppresses the metastatic potential of NSCLC through: (i) upregulation of pro-apoptotic Caspase-9 and Caspase-3, (ii) induction of cytosolic cytochrome c, (iii) modulation of pro-inflammatory cytokines (GRO, MCP-1, IL-8, and IL-6) and anticancer IL-24 in NSCLC subtypes, and (iv) upregulation of tumor suppressors, PKR (protein kinase R) and OAS (2′5′ oligoadenylate synthetase). In silico analysis showed that Lys296 of PKR and Lys66 of OAS interact with Hiltonol. These Lys residues are purportedly involved in the catalytic/signaling activity of the tumor suppressors. Furthermore, knockdown of PKR/OAS abrogated the anticancer action of Hiltonol, provoking survival of cancer cells. Ex vivo analysis of NSCLC patient tissues corroborated that loss of PKR and OAS is associated with cancer advancement. Altogether, our findings unraveled the significance of studying tumor biobank tissues, which suggests PKR and OAS as precision oncological suppressor candidates to be targeted by this novel Hiltonol+++ cocktail which represents a prospective drug for development into a potent and tailored therapy for NSCLC subtypes.

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Section: Hiltonol +++ Suppressed Lung Cancer Cell Proliferation Throumentioning

confidence: 99%

Section: In Silico Analysis Showed Interaction Between Hiltonol and Pmentioning

confidence: 99%

Section: Computational Prediction Of Hiltonol Binding Sites In Pkr Anmentioning

confidence: 99%

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Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment

Chang

Zhang

et al. 2021

IJMS

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“…We performed a molecular docking analysis between hypericin and the dimer/monomer of PEDV 3CLpro/3CLpro mut (Met6Ala, Ile151Ala, Asn152Ala, and Gln295Ala in dimer and Asn141Ala, Ile164Ala, Glu165Ala, Asp186Ala, Gln187Ala, and Gln191Ala in monomer) with AutoDock 4.2 (version 4.2.6) to predict the binding of hypericin to PEDV 3CLpro [ 31 ]. Briefly, we used 3CLpro/3CLpro mut monomer–dimer structure as a receptor (corrected it with removing co-crystallized waters and adding charges and hydrogens) and hypericin as a ligand (adding charges).…”

Section: Methodsmentioning

confidence: 99%

Hypericin Inhibit Alpha-Coronavirus Replication by Targeting 3CL Protease

Zhang

Chen

Zou

et al. 2021

Viruses

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The porcine epidemic diarrhea virus (PEDV) is an Alphacoronavirus (α-CoV) that causes high mortality in infected piglets, resulting in serious economic losses in the farming industry. Hypericin is a dianthrone compound that has been shown as an antiviral activity on several viruses. Here, we first evaluated the antiviral effect of hypericin in PEDV and found the viral replication and egression were significantly reduced with hypericin post-treatment. As hypericin has been shown in SARS-CoV-2 that it is bound to viral 3CLpro, we thus established a molecular docking between hypericin and PEDV 3CLpro using different software and found hypericin bound to 3CLpro through two pockets. These binding pockets were further verified by another docking between hypericin and PEDV 3CLpro pocket mutants, and the fluorescence resonance energy transfer (FRET) assay confirmed that hypericin inhibits the PEDV 3CLpro activity. Moreover, the alignments of α-CoV 3CLpro sequences or crystal structure revealed that the pockets mediating hypericin and PEDV 3CLpro binding were highly conserved, especially in transmissible gastroenteritis virus (TGEV). We then validated the anti-TGEV effect of hypericin through viral replication and egression. Overall, our results push forward that hypericin was for the first time shown to have an inhibitory effect on PEDV and TGEV by targeting 3CLpro, and it deserves further attention as not only a pan-anti-α-CoV compound but potentially also as a compound of other coronaviral infections.

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“…However, the antiviral activity in these large-scale screens may, in part, be cell-line specific (Hoffmann et al, 2020), and therefore of unclear clinical relevance. Another approach to screen potential drugs for repurposing is to perform docking (Goodsell et al, 2020) of clinical-stage or FDA-approved drugs to the SARS-CoV-2 proteome (S. Ortega et al, 2020). However, selection of the correct binding sites on the target proteins is crucial and difficult as protein surface cavities far exceed actual ligand binding sites that modulate function (Gupta et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Identification of evolutionarily stable functional and immunogenic sites across the SARS-CoV-2 proteome and the greater coronavirus family

Wang

Konecki

Marciano

et al. 2021

Preprint

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Since the first recognized case of COVID-19, more than 100 million people have been infected worldwide. Global efforts in drug and vaccine development to fight the disease have yielded vaccines and drug candidates to cure COVID-19. However, the spread of SARS-CoV-2 variants threatens the continued efficacy of these treatments. In order to address this, we interrogate the evolutionary history of the entire SARS-CoV-2 proteome to identify evolutionarily conserved functional sites that can inform the search for treatments with broader coverage across the coronavirus family. Combining this information with the mutations observed in the current COVID-19 outbreak, we systematically and comprehensively define evolutionarily stable sites that may provide useful drug and vaccine targets and which are less likely to be compromised by the emergence of new virus strains. Several experimentally-validated effective drugs interact with these proposed target sites. In addition, the same evolutionary information can prioritize cross reactive antigens that are useful in directing multi-epitope vaccine strategies to illicit broadly neutralizing immune responses to the betacoronavirus family. Although the results are focused on SARS-CoV-2, these approaches stem from evolutionary principles that are agnostic to the organism or infective agent.

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TheAutoDocksuite at 30

Cited by 107 publications

References 63 publications

Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment

Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment

Hypericin Inhibit Alpha-Coronavirus Replication by Targeting 3CL Protease

Identification of evolutionarily stable functional and immunogenic sites across the SARS-CoV-2 proteome and the greater coronavirus family

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