A novel compound active against SARS-CoV-2 targeting uridylate-specific endoribonuclease (NendoU/NSP15): <i>in silico</i> and <i>in vitro</i> investigations

Kumar, Sumit; Gupta, Yash; Zak, Samantha E.; Upadhyay, Charu; Sharma, Neha; Herbert, Andrew S.; Durvasula, Ravi; Потемкин, В. А.; Dye, John M.; Poonam, .; Kempaiah, Prakasha; Rathi, Brijesh

doi:10.1039/d1md00202c

Cited by 21 publications

(13 citation statements)

References 26 publications

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“…19 Recently, several HEA analogs have been reported as efficacious against the SARS-CoV-2 virus. 20–22 FDA-approved protease inhibitors of HIV 18 also support the importance of the HEA pharmacophore (Fig. 1).…”

Section: Introductionmentioning

confidence: 78%

A potent candidate against Zika virus infection: Synthesis, bioactivity, radiolabeling and biodistribution studies

Kumar¹,

Sharma²,

Dantas³

et al. 2022

New J. Chem.

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Section: Introductionmentioning

confidence: 78%

A potent candidate against Zika virus infection: Synthesis, bioactivity, radiolabeling and biodistribution studies

Kumar¹,

Sharma²,

Dantas³

et al. 2022

New J. Chem.

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“…As shown above, all five compounds that we found by GLIDE are nucleotide analogues as well. Very recently, Kumar et al carried out in silico and in vitro screening for active compounds from their in-house libraries targeting to Nsp15 and identified ‘Compound IV’ ((2S,3S)-3-amino-1-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-4-phenylbutan-2-ol) as the best one in in vitro assays 37 . Of these, functional groups of Compound IV share analogous interactions with Nsp15 in Pocket A/B with those of the compound of pose 4 that shows the lowest .…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the hexamerization of SARS-CoV-2 endoribonuclease and modeling of RNA structures bound to the hexamer

Tran

Taira

Ogawa

et al. 2022

Sci Rep

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Non-structural protein 15 (Nsp15) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) forms a homo hexamer and functions as an endoribonuclease. Here, we propose that Nsp15 activity may be inhibited by preventing its hexamerization through drug binding. We first explored the stable conformation of the Nsp15 monomer as the global free energy minimum conformation in the free energy landscape using a combination of parallel cascade selection molecular dynamics (PaCS-MD) and the Markov state model (MSM), and found that the Nsp15 monomer forms a more open conformation with larger druggable pockets on the surface. Targeting the pockets with high druggability scores, we conducted ligand docking and identified compounds that tightly bind to the Nsp15 monomer. The top poses with Nsp15 were subjected to binding free energy calculations by dissociation PaCS-MD and MSM (dPaCS-MD/MSM), indicating the stability of the complexes. One of the identified pockets, which is distinctively bound by inosine analogues, may be an alternative binding site to stabilize viral RNA binding and/or an alternative catalytic site. We constructed a stable RNA structure model bound to both UTP and alternative binding sites, providing a reasonable proposed model of the Nsp15/RNA complex.

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“…Another recent study identified additional FDA‐approved drugs that can inhibit Nsp15 activity in vitro [ 86 ]. Using high‐resolution structures as the starting point, in silico screening approaches have also identified numerous putative Nsp15 inhibitors [ 87 , 88 , 89 , 90 , 91 , 92 ].…”

Section: Inhibitors Of Nsp14 and Nsp15mentioning

confidence: 99%

Recent insights into the structure and function of coronavirus ribonucleases

et al. 2022

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Coronaviruses use approximately two‐thirds of their 30‐kb genomes to encode nonstructural proteins (nsps) with diverse functions that assist in viral replication and transcription, and evasion of the host immune response. The SARS‐CoV‐2 pandemic has led to renewed interest in the molecular mechanisms used by coronaviruses to infect cells and replicate. Among the 16 Nsps involved in replication and transcription, coronaviruses encode two ribonucleases that process the viral RNA—an exonuclease (Nsp14) and an endonuclease (Nsp15). In this review, we discuss recent structural and biochemical studies of these nucleases and the implications for drug discovery.

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A novel compound active against SARS-CoV-2 targeting uridylate-specific endoribonuclease (NendoU/NSP15): in silico and in vitro investigations

Abstract: NendoU (NSP15) is an Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond. Our in-house library was subjected to high throughput virtual screening (HTVS) to identify compounds...

Cited by 21 publications

References 26 publications

A potent candidate against Zika virus infection: Synthesis, bioactivity, radiolabeling and biodistribution studies

A potent candidate against Zika virus infection: Synthesis, bioactivity, radiolabeling and biodistribution studies

Inhibition of the hexamerization of SARS-CoV-2 endoribonuclease and modeling of RNA structures bound to the hexamer

Recent insights into the structure and function of coronavirus ribonucleases

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