Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease.
05 May 2020-Journal of Biomolecular Structure & Dynamics (J Biomol Struct Dyn)-Vol. 39, Iss: 9, pp 1-16
TL;DR: This work has identified several natural molecules like δ-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 MPro.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected over 2.5 million individuals with a mortality rate ranging from 5 to 10%. There are several efforts going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (MPro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of MPro, we have performed phylogenetic and Sequence Similarity Network analysis, that depicted divergence of Coronaviridae MPro in five clusters specific to viral hosts. This clustering was corroborated with the comparison of MPro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. These attributes can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 MPro. In agreement with this, we performed screening of ∼7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 MPro as the primary target. We identified several natural molecules like δ-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 MPro. Intrestingly, these molecules also showed strong binding with other potential targets of SARS-CoV-2 infection like viral receptor human angiotensin-converting enzyme 2 (hACE-2) and RNA dependent RNA polymerase (RdRp). We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.
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TL;DR: A comparative study of the use of the recent deep learning models to deal with detection and classification of coronavirus pneumonia found out that theUse of inception_Resnet_V2 and Densnet201 provide better results compared to other models used in this work.
Abstract: Coronavirus is still the leading cause of death worldwide. There are a set number of COVID-19 test units accessible in emergency clinics because of the expanding cases daily. Therefore, it is important to implement an automatic detection and classification system as a speedy elective finding choice to forestall COVID-19 spreading among individuals. Medical images analysis is one of the most promising research areas, it provides facilities for diagnosis and making decisions of a number of diseases such as Coronavirus. This paper conducts a comparative study of the use of the recent deep learning models (VGG16, VGG19, DenseNet201, Inception_ResNet_V2, Inception_V3, Resnet50, and MobileNet_V2) to deal with detection and classification of coronavirus pneumonia. The experiments were conducted using chest X-ray & CT dataset of 6087 images (2780 images of bacterial pneumonia, 1493 of coronavirus, 231 of Covid19, and 1583 normal) and confusion matrices are used to evaluate model performances. Results found out that the use of inception_Resnet_V2 and Densnet201 provide better results compared to other models used in this work (92.18% accuracy for Inception-ResNetV2 and 88.09% accuracy for Densnet201).Communicated by Ramaswamy H. Sarma.
245 citations
Cites background from "Discovery of potential multi-target..."
...…2020; Sourav et al., 2020; Umesh et al., 2020), Covid19 is a respiratory disease that is caused by the new coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) 2019 (Abdelli et al., 2020; Rakesh et al., 2020; Rameez et al., 2020; World Health Organization, 2020)....
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TL;DR: Flavonoids and their derivative may represent target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections.
222 citations
TL;DR: This study shows that these three polyphenols from green tea can be used as potential inhibitors against SARS CoV-2 Mpro and are promising drug candidates for COVID-19 treatment.
Abstract: Coronavirus disease 2019 (COVID-19) is a viral respiratory disease which caused global health emergency and announced as pandemic disease by World Health Organization Lack of specific drug molecul
212 citations
Cites background from "Discovery of potential multi-target..."
...Interestingly, many antiviral phytochemicals, bioactive compounds from Moroccan medicinal plants (Crocin, Digitoxigenin and b-Eudesmol) and chemical compounds from Indian spices (Carnosol, Rosmanol and Arjunglucoside-I) are proposed to be effective SARS CoV-2 Mpro inhibitors (Aanouz et al., 2020; Das et al., 2020; Enmozhi et al., 2020; Gyebi et al., 2020; Islam et al., 2020; Joshi et al., 2020; Umesh et al., 2020)....
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...…and b-Eudesmol) and chemical compounds from Indian spices (Carnosol, Rosmanol and Arjunglucoside-I) are proposed to be effective SARS CoV-2 Mpro inhibitors (Aanouz et al., 2020; Das et al., 2020; Enmozhi et al., 2020; Gyebi et al., 2020; Islam et al., 2020; Joshi et al., 2020; Umesh et al., 2020)....
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TL;DR: Molecular docking studies using 10 potential naturally occurring compounds against the SARS-CoV-2 spike protein and compared their affinity with an FDA approved repurposed drug hydroxychloroquine revealed that these molecules bind with the hACE2-S complex with low binding free energy, and ADME analysis suggested that they consist of drug-likeness property, which may be further explored as anti-SARS- CoV- 2 agents.
Abstract: Spike glycoprotein, a class I fusion protein harboring the surface of SARS-CoV-2 (SARS-CoV-2S), plays a seminal role in the viral infection starting from recognition of the host cell surface receptor, attachment to the fusion of the viral envelope with the host cells. Spike glycoprotein engages host Angiotensin-converting enzyme 2 (ACE2) receptors for entry into host cells, where the receptor recognition and attachment of spike glycoprotein to the ACE2 receptors is a prerequisite step and key determinant of the host cell and tissue tropism. Binding of spike glycoprotein to the ACE2 receptor triggers a cascade of structural transitions, including transition from a metastable pre-fusion to a post-fusion form, thereby allowing membrane fusion and internalization of the virus. From ancient times people have relied on naturally occurring substances like phytochemicals to fight against diseases and infection. Among these phytochemicals, flavonoids and non-flavonoids have been the active sources of different anti-microbial agents. We performed molecular docking studies using 10 potential naturally occurring compounds (flavonoids/non-flavonoids) against the SARS-CoV-2 spike protein and compared their affinity with an FDA approved repurposed drug hydroxychloroquine (HCQ). Further, our molecular dynamics (MD) simulation and energy landscape studies with fisetin, quercetin, and kamferol revealed that these molecules bind with the hACE2-S complex with low binding free energy. The study provided an indication that these molecules might have the potential to perturb the binding of hACE2-S complex. In addition, ADME analysis also suggested that these molecules consist of drug-likeness property, which may be further explored as anti-SARS-CoV-2 agents. Communicated by Ramaswamy H. Sarma.
175 citations
Cites background from "Discovery of potential multi-target..."
...The world population is facing a severe mass annihilation due to the rise of a global pandemic named Coronavirus Disease 2019 (COVID-19) (Boopathi et al., 2020; Chatterjee et al., 2020; Joshi et al., 2020; Kirchdoerfer et al., 2016)....
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TL;DR: The most relevant existing literature about modeling strategies against the virus is compiled to help modelers to navigate this fast-growing literature and keep an eye on future outbreaks, where the modelers can find the most relevant strategies used in an emergence situation as the current one to help in fighting future pandemics.
170 citations
Cites background from "Discovery of potential multi-target..."
...Mpro virtual screening d-viniferin, myricitrin, afzelin, hesperidin [100] Jiang et al....
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References
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TL;DR: An advanced version of the Molecular Evolutionary Genetics Analysis software, which currently contains facilities for building sequence alignments, inferring phylogenetic histories, and conducting molecular evolutionary analysis, is released, which enables the inference of timetrees, as it implements the RelTime method for estimating divergence times for all branching points in a phylogeny.
Abstract: We announce the release of an advanced version of the Molecular Evolutionary Genetics Analysis (MEGA) software, which currently contains facilities for building sequence alignments, inferring phylogenetic histories, and conducting molecular evolutionary analysis. In version 6.0, MEGA now enables the inference of timetrees, as it implements the RelTime method for estimating divergence times for all branching points in a phylogeny. A new Timetree Wizard in MEGA6 facilitates this timetree inference by providing a graphical user interface (GUI) to specify the phylogeny and calibration constraints step-by-step. This version also contains enhanced algorithms to search for the optimal trees under evolutionary criteria and implements a more advanced memory management that can double the size of sequence data sets to which MEGA can be applied. Both GUI and command-line versions of MEGA6 can be downloaded from www.megasoftware.net free of charge.
37,956 citations
"Discovery of potential multi-target..." refers methods in this paper
...A total of 57 sequences (Supplementary Data 4) were selected for the phylogenetic analysis by maximum likelihood (ML) method using MEGA6 software (Tamura et al., 2013)....
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TL;DR: Two unusual extensions are presented: Multiscale, which adds the ability to visualize large‐scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales.
Abstract: The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.
35,698 citations
"Discovery of potential multi-target..." refers methods in this paper
...The structural backbone and active site conservation representation was obtained by Chimera 1.10.2 software (Pettersen et al., 2004) ....
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...The structural backbone and active site conservation representation was obtained by Chimera 1.10.2 software (Pettersen et al., 2004)....
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01 Jan 2013
TL;DR: The Molecular Evolutionary Genetics Analysis (MEGA) software as discussed by the authors provides facilities for building sequence alignments, inferring phylogenetic histories, and conducting molecular evolutionary analysis, including the inference of timetrees.
Abstract: We announce the release of an advanced version of the Molecular Evolutionary Genetics Analysis (MEGA) software, which currently contains facilities for building sequence alignments, inferring phylogenetic histories, and conducting molecular evolutionary analysis. In version 6.0, MEGA now enables the inference of timetrees, as it implements the RelTime method for estimating divergence times for all branching points in a phylogeny. A new Timetree Wizard in MEGA6 facilitates this timetree inference by providing a graphical user interface (GUI) to specify the phylogeny and calibration constraints step-by-step. This version also contains enhanced algorithms to search for the optimal trees under evolutionary criteria and implements a more advanced memory management that can double the size of sequence data sets to which MEGA can be applied. Both GUI and command-line versions of MEGA6 can be downloaded from www. megasoftware.net free of charge.
30,478 citations
TL;DR: AutoDock Vina achieves an approximately two orders of magnitude speed‐up compared with the molecular docking software previously developed in the lab, while also significantly improving the accuracy of the binding mode predictions, judging by tests on the training set used in AutoDock 4 development.
Abstract: AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user.
20,059 citations
"Discovery of potential multi-target..." refers methods in this paper
...Virtual screening using autodock vina and ADME studies Prepared receptor molecules from the custom-made libraries were set for the virtual screening by AutoDock Vina based Lamarckian Genetic Algorithm (LGA) parameter for ligand tethering of the proteins using 10 runs criteria (Trott & Olson, 2010) ....
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TL;DR: AutoDock4 incorporates limited flexibility in the receptor and its utility in analysis of covalently bound ligands is reported, using both a grid‐based docking method and a modification of the flexible sidechain technique.
Abstract: We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique.
15,616 citations
"Discovery of potential multi-target..." refers methods in this paper
...All the molecules were checked for stereochemical properties and then converted to .pdbqt format using Autodock Tools (Morris et al., 2009)....
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...Grid for MPro was set around active site residues H41 and C145 with dimension on 36 56 x 40Å using the AutoGrid program of AutoDock Tools (Morris et al., 2009)....
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