Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses

Luttens, Andreas; Gullberg, Hjalmar; Abdurakhmanov, Eldar; Vo, Duy Duc; Akaberi, Dario; Talibov, V.; Nekhotiaeva, Natalia; Vangeel, Laura; Jonghe, Steven De; Jochmans, Dirk; Krambrich, Janina; Taş, Ali; Lundgren, Bo; Gravenfors, Ylva; Craig, Alexander J.; Atilaw, Yoseph; Sandström, Anna; Moodie, Lindon W. K.; Lundkvist, Åke; Hemert, Martijn J. van; Neyts, Johan; Lennerstrand, Johan; Kihlberg, Jan; Sandberg, Kristian; Danielson, U. Helena; Carlsson, Jens

doi:10.1021/jacs.1c08402

Cited by 155 publications

(168 citation statements)

References 68 publications

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“…The first of these pertains tothe vastness of the chemical space being explored and its impact on the throughput and practical utility of the prevailing methods. For example, the use of docking or molecular simulation methods to screen on the order of 10 8 to 10 9 commercially available compounds, would incur a prohibitively high computational cost, estimated to reach 10 CPU years 21 per target (as opposed to screening of less than a thousand machine-designed de novo candidates via docking in the present study).…”

Section: Discussionmentioning

confidence: 98%

“…The second challenge is availability of critical information: while methods such as pharmacophore modeling and molecular docking have been used successfully in virtual screening or design of molecules 21,23,[29][30][31] , such approaches generally rely upon initial design constructs obtained from available crystal structure(s) of a target protein bound to a candidate compound or fragment hits. Such information is not guaranteed to be available for all drug targets of interest and may take months to derive experimentally, and consequently these approaches are not broadly applicable to the case where such structures are unknown.…”

Section: Discussionmentioning

confidence: 99%

“…These results are shown in Table 1. In this category, specifically, we considered the following: an aminipyridine hit identified in the COVID-19 Moonshot initiative 20 , X77 identified using ultralarge docking 21 , the oral inhibitor S-217622 from reference 22 Nirmatrelvir in PAXLOVID 19 , an α-ketoamide inhibitor (Compound 21 from Zhang, et al 23 ), and Molnupiravir 24 . Consistently, the CogMol-designed inhibitors show high dissimilarity (as indicated by a low Tanimoto similarity around 0.1) to existing SARS-CoV-2 M pro inhibitors.…”

Section: Novelty Of the De Novo Designs And Comparison With Known Sar...mentioning

confidence: 99%

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Accelerating Inhibitor Discovery With A Deep Generative Foundation Model: Validation for SARS-CoV-2 Drug Targets

Chenthamarakshan¹,

Hoffman²,

Owen³

et al. 2022

Preprint

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The COVID-19 pandemic has highlighted the urgency for developing more efficient molecular discovery pathways. As exhaustive exploration of the vast chemical space is infeasible, discovering novel inhibitor molecules for emerging drug-target proteins is challenging, particularly for targets with unknown structure or ligands. We demonstrate the broad utility of a single deep generative framework toward discovering novel drug-like inhibitor molecules against two distinct SARS-CoV-2 targets -the main protease (M pro ) and the receptor binding domain (RBD) of the spike protein. To perform target-aware design, the framework employs a target sequence-conditioned sampling of novel molecules from a generative model. Micromolar-level in vitro inhibition was observed for two candidates (out of four synthesized) for each target. The most potent spike RBD inhibitor also emerged as a rare non-covalent antiviral with broad-spectrum activity against several SARS-CoV-2 variants in live virus neutralization assays. These results show that a broadly deployable machine intelligence framework can accelerate hit discovery across different emerging drug-targets.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Novelty Of the De Novo Designs And Comparison With Known Sar...mentioning

confidence: 99%

See 1 more Smart Citation

Accelerating Inhibitor Discovery With A Deep Generative Foundation Model: Validation for SARS-CoV-2 Drug Targets

Chenthamarakshan¹,

Hoffman²,

Owen³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…To date, several studies have contributed to thoroughly characterising the nature of the shallow and solvent-exposed catalytic site of the SARS-CoV-2 28 , which has proven to be readily investigable with both time-dependent and time-independent structure based-approaches such as molecular docking 29 and molecular dynamics 30 , leading to the development of compounds with affinities in the low nanomolar range 31 , 32 .…”

Section: Discussionmentioning

confidence: 99%

Bat coronaviruses related to SARS-CoV-2: what about their 3CL proteases (MPro)?

Pavan

Bassani

Sturlese

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Despite a huge effort by the scientific community to determine the animal reservoir of SARS-CoV-2, which led to the identification of several SARS-CoV-2-related viruses both in bats and in pangolins, the origin of SARS-CoV-2 is still not clear. Recently, Temmam et al. reported the discovery of bat coronaviruses with a high degree of genome similarity with SARS-CoV-2, especially concerning the RBDs of the S protein, which mediates the capability of such viruses to enter and therefore infect human cells through a hACE2-dependent pathway. These viruses, especially the one named BANAL-236, showed a higher affinity for the hACE2 compared to the original strain of SARS-CoV-2. In the present work, we analyse the similarities and differences between the 3CL protease (main protease, M pro ) of these newly reported viruses and SARS-CoV-2, discussing their relevance relative to the efficacy of existing therapeutic approaches against COVID-19, particularly concerning the recently approved orally available Paxlovid, and the development of future ones.

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“…Its biological function in the viral replication cycle, along with the absence of a closely related human homologue, establish M pro as a propitious drug target. The structure determination of SARS-CoV-2 M pro sparked the development of several classes of inhibitors that bind either to the active site and covalently modify the catalytic cysteine or to allosteric sites (11)(12)(13)(14)(15)(16)(17)(18). These efforts culminated in the design of Paxlovid TM (Pfizer), an orally administered FDA-approved antiviral drug which contains Nirmatrelvir, an inhibitor targeting SARS-CoV-2 M pro (19).…”

Section: Introductionmentioning

confidence: 99%

Redox regulation of the SARS-CoV-2 main protease provides new opportunities for drug design

Tittmann

Funk

Poschmann

et al. 2022

Preprint

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Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for stopping the current COVID-19 pandemic and preventing future outbreaks. The SARS-CoV-2 main protease (Mpro), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that Mpro is subject to redox regulation and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include sulfenylation, disulfide formation between the catalytic cysteine and a proximal cysteine, and generation of an allosteric lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and possess antiviral activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS and SARS-CoV, indicating their potential as common druggable sites.

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Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses

Cited by 155 publications

References 68 publications

Accelerating Inhibitor Discovery With A Deep Generative Foundation Model: Validation for SARS-CoV-2 Drug Targets

Accelerating Inhibitor Discovery With A Deep Generative Foundation Model: Validation for SARS-CoV-2 Drug Targets

Bat coronaviruses related to SARS-CoV-2: what about their 3CL proteases (MPro)?

Redox regulation of the SARS-CoV-2 main protease provides new opportunities for drug design

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