A critical overview of computational approaches employed for COVID-19 drug discovery

Muratov, Eugene; Amaro, Rommie E.; Andrade, Carolina Horta; Brown, Nathan; Ekins, Sean; Fourches, Denis; Isayev, Olexandr; Kozakov, Dima; Medina-Franco, José L.; Merz, Kenneth M.; Oprea, Tudor I.; Poroikov, Vladimir; Schneider, Gisbert; Todd, Matthew H.; Varnek, Alexandre; Winkler, David A.; Zakharov, Alexey; Cherkasov, Artem; Tropsha, Alexander

doi:10.1039/d0cs01065k

Cited by 143 publications

(101 citation statements)

References 187 publications

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“…Main protease (M pro ) is one such structural protein emerging as a promising target for antiviral drug development due to is role in viral replication and transcription 10 – 14 . Numerous drug discovery projects are currently pursued to identify potent inhibitors through the combination of computer-aided drug designing approaches and biochemical assays 15 . Structure-based virtual screening for identifying potential inhibitors from the collection of FDA-approved antiviral is extensively carried out to reduce the burden of designing new molecules and unknown fate in ADME/T properties and clinical trials 16 – 18 .…”

Section: Introductionmentioning

confidence: 99%

Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

Patel

Jani

Jaiswal

et al. 2021

Sci Rep

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Novel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.

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Section: Introductionmentioning

confidence: 99%

Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

Patel

Jani

Jaiswal

et al. 2021

Sci Rep

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“…[38] At this point, it is worth to stress that Δ G BIND values obtained by this approach are somewhat overestimated in absolute terms. This is a known limitation of the employed MM-GBSA approach, as extensively discussed in a recent review by Homeyer and Gohlke,[51] which also underlined its huge potential in predicting relative binding energies in biomolecular complexes [39,42,43,51], precisely how this approach was used and discussed here. In this context, our analysis successfully reproduced the higher affinity of the SA strain, being in excellent agreement with experimental data,[40] thus further validating our computational setup.…”

Section: Resultsmentioning

confidence: 99%

“…The SARS-CoV-2 infiltrates human cells through an interaction between the virus S1 spike protein and the ACE2 receptor, a mechanism that has been extensively studied and characterized using various structural [35,36] and computational [37][38][39] techniques. Therefore, we felt it was useful to employ our computational setup to find relevant binding poses and dynamical features of the spike protein-ACE2 complexes and benchmark the obtained results with relevant literature data.…”

Section: African Variant B1351mentioning

confidence: 99%

Relationship between COVID-19 infection and neurodegeneration: Computational insight into interactions between the SARS-CoV-2 spike protein and the monoamine oxidase enzymes

Hok

Rimac

Mavri

et al. 2021

Preprint

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Although COVID-19 has been primarily associated with pneumonia, recent data show that its causative agent, the SARS-CoV-2 coronavirus, can infect many vital organs beyond the lungs, including the heart, kidneys and the brain. The literature agrees that COVID-19 is likely to have long-term mental health effects on infected individuals, which signifies a need to understand the role of the virus in the pathophysiology of brain disorders that is currently unknown and widely debated. Our docking and molecular dynamic simulations show that the affinity of the spike protein from the wild type (WT) and the South African B.1.351 (SA) variant towards the MAO enzymes is comparable to that for its ACE2 receptor. This allows for the WT/SA∙∙∙MAO complex formation, which changes MAO affinities for their neurotransmitter substrates, thus consequently impacting the rates of their metabolic conversion and misbalancing their levels. Knowing that this fine regulation is strongly linked with the etiology of various brain pathologies, these results are the first to highlight the possibility that the interference with the brain MAO catalytic activity is responsible for the increased neurodegenerative illnesses following a COVID-19 infection, thus placing a neurobiological link between these two conditions in the spotlight. Since the obtained insight suggests that a more contagious SA variant causes even larger disturbances, and with new and more problematic strains likely emerging in the near future, we firmly advise that the presented prospect of the SARS-CoV-2 induced neurological complications should not be ignored, but rather requires further clinical investigations to achieve an early diagnosis and timely therapeutic interventions.

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“…In silico computational research efforts are productive for the structures and interactions of the key proteins, especially at the earliest stages when no structures have yet been reported from experimental studies. Despite an unprecedented number of studies having been published in the last one and half years on computer-aided drug discovery 5 , only one drug has arisen from computational studies 6 -baricitinib -which has been approved for emergency use to treat COVID-19, in combination with remdesivir. Both of the drugs are repurposed medications: baricitinib is a kinase inhibitor originally designed to treat rheum atoid arthritis; remdesivir is a broadspectrum antiviral medication originally developed to treat hepatitis C, and subsequently investigated for Ebola.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease

Wan

Bhati

Wade

et al. 2021

Preprint

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Although researchers have been working tirelessly since the COVID-19 outbreak, so far only two drugs -remdesivir and ronapreve -have been approved for use in some countries which directly target the SARS-CoV-2 virus. Given the slow pace and substantial costs of new drug discovery and development, together with the urgency of the matter, repurposing of existing drugs for the ongoing disease is an attractive proposition. In a recent study, a high-throughput x-ray crystallographic screen was performed for a selection of drugs which have been approved or are in clinical trials. Thirty-seven compounds have been identified from drug libraries all of which bind to the SARS-CoV-2 main protease (3CL pro ). In the current study, we use molecular dynamics simulation and an ensemble-based free energy approach, namely, enhanced sampling of molecular dynamics with approximation of continuum solvent (ESMACS), to investigate a subset of the aforementioned compounds. The drugs studied here are highly diverse, interacting with different binding sites and/or subsites of 3CL pro . The predicted free energies are compared with experimental results wherever they are available and they are found to be in excellent agreement. Our study also provides detailed energetic insights into the nature of the associated drug−protein binding, in turn shedding light on the design and discovery of potential drugs.

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A critical overview of computational approaches employed for COVID-19 drug discovery

Abstract: We cover diverse methodologies, computational approaches, and case studies illustrating the ongoing efforts to develop viable drug candidates for treatment of COVID-19.

Cited by 143 publications

References 187 publications

Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

Relationship between COVID-19 infection and neurodegeneration: Computational insight into interactions between the SARS-CoV-2 spike protein and the monoamine oxidase enzymes

Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease

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