COVID-19: CADD to the rescue

Onawole, Abdulmujeeb T.; Sulaiman, Kazeem O.; Kolapo, Temitope U.; Akinde, Fatimo O.; Adegoke, Rukayat O.

doi:10.1016/j.virusres.2020.198022

Cited by 27 publications

(12 citation statements)

References 64 publications

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“…3-Galloylcatechin was nonetheless the only exception inhibiting CYP3A4 and CYP2C19 isoforms ( Table 4 ). This inhibition could lead to the accumulation of drugs metabolised by these CYP isoforms and, hence, drug toxicity may occur [ 86 ]. A half-life of 1.534, 2.11, and 1.483 hours as well as a clearance rate of 1.204, 1.015, and 1.232 mL/min/kg were the respective elimination properties of 3-galloylcatechin, proanthocyanidin B1, and luteolin 7-galactoside ( Table 4 ).…”

Section: Resultsmentioning

confidence: 99%

Computer-Aided Analysis of Multiple SARS-CoV-2 Therapeutic Targets: Identification of Potent Molecules from African Medicinal Plants

Iheagwam

Rotimi

2020

Scientifica

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The COVID-19 pandemic, which started in Wuhan, China, has spread rapidly over the world with no known antiviral therapy or vaccine. Interestingly, traditional Chinese medicine helped in flattening the pandemic curve in China. In this study, molecules from African medicinal plants were analysed as potential candidates against multiple SARS-CoV-2 therapeutic targets. Sixty-five molecules from the ZINC database subset (AfroDb Natural Products) were virtually screened with some reported repurposed therapeutics against six SARS-CoV-2 and two human targets. Molecular docking, druglikeness, absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the best hits were further simulated. Of the 65 compounds, only three, namely, 3-galloylcatechin, proanthocyanidin B1, and luteolin 7-galactoside found in almond (Terminalia catappa), grape (Vitis vinifera), and common verbena (Verbena officinalis), were able to bind to all eight targets better than the reported repurposed drugs. The findings suggest these molecules may play a role as therapeutic leads in tackling this pandemic due to their multitarget activity.

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Section: Resultsmentioning

confidence: 99%

Computer-Aided Analysis of Multiple SARS-CoV-2 Therapeutic Targets: Identification of Potent Molecules from African Medicinal Plants

Iheagwam

Rotimi

2020

Scientifica

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“…Top 100 compounds were reported with inhibitory activity in mM. 100 lead compounds from ZINC15 and CAS database [ 115 ] Pharmacophore (vROCS (OpenEye)) and Docking study followed by VS (AutoDock 4.2) Four pharmacophores (OEW, remdesivir, hydroxychloroquine and N3) and 50,000 natural compounds from ZINC database for VS 6LU7 and 6Y7M Pharmacophore and docking based virtual screening performed employing natural compounds of ZINC database targeting SARS-CoV-2M protease 11 ligands as (ZINC1845382, ZINC1875405, ZINC2092396, ZINC2104424, ZINC44018332, ZINC2101723, ZINC2094526, ZINC2094304, ZINC2104482, ZINC3984030, and ZINC1531664) [ 116 ] Sequence analysis and homology modeling followed by VS employed docking (AutoDock VINA) and later using machine learning technique CNN (BindScope) MCULE database (44,704,142) 6VSB 44 million compounds were screened to find potential inhibitor able to inhibit the surface glycoprotein responsible for virus entry and binding 3 molecules (benzylfuran-2(5H)-one); ((2,5-difluorophenyl)thio)-2,2-difluoroacetic acid) and (2-methylfuran-3-yl)methanesulfonyl fluoride) [ 117 ] Similarity searching and Docking (Autodock Vina, version 1.1.2 and MOE v.2019) and ADMET profiling (SwissADME) FooDB (22,880), Dark Chemical Matter (DCM) (139,329), ZINC (top 10 hit from literature), Actives (11) 6LU7, 5N5O Consensus VS of DCM and Food Chemicals as potential inhibitors of SARS-CoV-2 M Pro 105 hits of which, three are commercially available [ 118 ] Docking (GLIDE-Schrodinger), MM-GBSA, ADMET profiling (pkCSM and ProTox-II), MD (DESMOND- Schrodinger) MolPort database (10,305) 6LU7, 6Y2E, 6Y2F, 6Y2G, 6M03, 6Y84, 5RF8, 5RG0, 5R8T Protein reliability analysis among 9 M pro proteins followed by VS through docking, MM-GBSA calculation, ADMET profiling and MD to find natural M pro inhibitors for SAS-COV-2 which is already commercially available for further testing 3 hits (two natural compounds MolPort-005-944-636 and MolPort-005-945-924, as well as a Noricaritin (MolPort-039-052-338) derived from Epimedium brevicornu Maxim) [ 119 ] …”

Section: In Silico Modeling Applied To Search the Future Drug Candidamentioning

confidence: 99%

Therapeutics for COVID-19: from computation to practices—where we are, where we are heading to

et al. 2020

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After the 1918 Spanish Flu pandemic caused by the H1N1 virus, the recent coronavirus disease 2019 (COVID-19) brought us to the time of serious global health catastrophe. Although no proven therapies are identified yet which can offer a definitive treatment of the COVID-19, a series of antiviral, antibacterial, antiparasitic, immunosuppressant drugs have shown clinical benefits based on repurposing theory. However, these studies are made on small number of patients, and, in majority of the cases, have been carried out as nonrandomized trials. As society is running against the time to combat the COVID-19, we present here a comprehensive review dealing with up-to-date information of therapeutics or drug regimens being utilized by physicians to treat COVID-19 patients along with in-depth discussion of mechanism of action of these drugs and their targets. Ongoing vaccine trials, monoclonal antibodies therapy and convalescent plasma treatment are also discussed. Keeping in mind that computational approaches can offer a significant insight to repurposing based drug discovery, an exhaustive discussion of computational modeling studies is performed which can assist target-specific drug discovery.

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“…The availability of plenty of structural data pertaining to the M-pro enzyme has triggered computer-aided drug design studies for either development of novel therapeutics or repurposing approved molecules. For the latter, virtual screening has been emerged as an effective computational technique for identifying compounds in libraries of small molecules that are most likely to bind to the target protein [45][46][47][48][49][50] .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SARS-CoV-2 Main Protease: A Repurposing Study That Targets the Dimer Interface of the Protein

Pekel¹,

Ilter

Şensoy³

2020

Preprint

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Coronavirus disease-2019 (COVID-19) was firstly reported in Wuhan, China, towards the end of 2019, and, unfortunately, within a short period of time, emerged as a pandemic. The spread and lethality rates of the COVID-19 have ignited studies that focus on the development of therapeutics for either treatment or prophylaxis purposes. In parallel, drug repurposing studies have also come into prominence. In this study, we aimed at having a holistic understanding of conformational and dynamical changes induced by an experimentally characterized inhibitor on main protease (M-pro) which would enable the discovery of novel inhibitors. To this end, we performed molecular dynamics simulations using crystal structures of apo and α-ketoamide-13b-bound M-pro homodimer. Analysis of trajectories pertaining to apo M-pro revealed a new target site, which is located at the homodimer interface, next to the catalytic dyad. Thereafter, we performed ensemble-based virtual screening by exploiting the ZINC and DrugBank databases and identified three candidate molecules, namely eluxadoline, diosmin, and ZINC02948810 that could invoke local and global conformational rearrangements which were also elicited by α-ketoamide-13b on the catalytic dyad of M-pro. Furthermore, ZINC23881687 was also discerned as a promising candidate due to its interaction with catalytically important residues Glu166 and Ser1. Last but not least, we could find another candidate, namely ZINC20425029, whose mode of action was different. It modulated the dynamical properties of catalytically important residue, Ala285 rather than the catalytic dyad. As such, this study presents valuable findings that might be used in the development of novel therapeutics against SARS-CoV-2 M-pro.

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COVID-19: CADD to the rescue

Cited by 27 publications

References 64 publications

Computer-Aided Analysis of Multiple SARS-CoV-2 Therapeutic Targets: Identification of Potent Molecules from African Medicinal Plants

Computer-Aided Analysis of Multiple SARS-CoV-2 Therapeutic Targets: Identification of Potent Molecules from African Medicinal Plants

Therapeutics for COVID-19: from computation to practices—where we are, where we are heading to

Inhibition of SARS-CoV-2 Main Protease: A Repurposing Study That Targets the Dimer Interface of the Protein

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