A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening

Gorgulla, Christoph; Das, Krishna Mohan; Leigh, Kendra E.; Cespugli, Marco; Fischer, Patrick D.; Wang, Zifu; Tesseyre, Guilhem; Pandita, Shreya; Shnapir, Alec; Calderaio, Anthony; Gechev, Minko; Rose, Alexander; Lewis, Noam; Hutcheson, Colin; Yaffe, Erez; Luxenburg, Roni; Herce, Henry D.; Durmaz, Vedat; Halazonetis, Thanos D.; Fackeldey, Konstantin; Patten, J.J.; Chuprina, Alexander; Dziuba, Igor; Plekhova, Alla; Moroz, Yurii S.; Radchenko, Dmytro S.; Tarkhanova, Olga; Yavnyuk, Irina; Gruber, Christian; Yust, Ryan; Payne, Dave; Näär, Anders M.; Namchuk, Mark; Davey, Robert A.; Wagner, Gerhard; Kinney, Jamie; Arthanari, Haribabu

doi:10.1016/j.isci.2020.102021

Cited by 72 publications

(73 citation statements)

References 226 publications

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“…Computational protocols for HTVS vary widely across existing SARS-CoV-2 M pro screens, from accurate but expensive simulations for MMGBSA/PBSA scoring to standard docking. Gorgulla et al 18 screened Enamine Real, a billion-scale combinatorial product library, against various SARS-CoV-2 targets using QuickVina W—a slightly less accurate but computationally efficient flavor of AutoDock Vina. 64 Acharya et al 13 also screened Enamine Real with Autodock-GPU.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor

Clyde

Galanie

Kneller

et al. 2021

J. Chem. Inf. Model.

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Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel noncovalent smallmolecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (M pro ) by employing a scalable high-throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this M pro inhibitor with an inhibition constant (K i ) of 2.9 μM (95% CI 2.2, 4.0). Furthermore, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of M pro forming stable hydrogen bond and hydrophobic interactions. We then used multiple μs-time scale molecular dynamics (MD) simulations and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by M pro , involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits M pro and offers a springboard for further therapeutic design.

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Section: Discussionmentioning

confidence: 99%

High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor

Clyde

Galanie

Kneller

et al. 2021

J. Chem. Inf. Model.

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“…Extensive research supports the relevance of CBR-PPAR dual targeting in the context of a broad range of pathologies. In fact, multitarget drugs can offer an improved therapeutic profile in complex diseases, as already occurs in multifactorial disorders such as cancer, neurodegenerative diseases, or psychiatric disorders [229]. In this sense, CB 2 R and PPARγ modulators are at the forefront of multitarget cannabinoid-related drugs.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System

Lago-Fernandez¹,

Zarzo-Arias²,

Jagerovic³

et al. 2021

IJMS

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Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.

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“…De novo M pro inhibitors have been identified by either in silico or physical screens. Three in silico screening studies are particularly relevant here: two studies that ranked more than one billion compounds each, but did not validate the identified hits 24 , 25 , and a third study that ranked 6.5 million compounds and validated seven top compounds, of which the most potent exhibited an IC50 of 4.2 μM in vitro 26 . Among the studies that employed physical screens to identify M pro inhibitors, one study screened a small library of chemical fragments for binding to M pro by X-ray crystallography and identified several hits, which, however, were not developed further 27 .…”

Section: Introductionmentioning

confidence: 99%

Non-covalent SARS-CoV-2 Mpro inhibitors developed from in silico screen hits

Rossetti

Ossorio

Rempel

et al. 2022

Sci Rep

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Mpro, the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify Mpro inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than five hundred compounds from the top-ranking hits of two very large in silico screens for on-demand synthesis. We then examined whether these compounds could bind to Mpro and inhibit its protease activity. Two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues. The compounds of the first chemotype denatured Mpro and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of Mpro. The most active compound from this chemotype inhibited Mpro in vitro with an IC50 value of 1 μM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to Mpro was determined by X-ray crystallography, revealing that it is a non-covalent inhibitor. We propose that the inhibitors described here could form the basis for medicinal chemistry efforts that could lead to the development of clinically relevant inhibitors.

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A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening

Cited by 72 publications

References 226 publications

High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor

High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor

Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System

Non-covalent SARS-CoV-2 Mpro inhibitors developed from in silico screen hits

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