Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like Protease (3CLpro) Structure: Virtual Screening Reveals Velpatasvir, Ledipasvir, and Other Drug Repurposing Candidates

Chen, Yu Wai; Yiu, Chin-Pang; Wong, Kwok Yin

doi:10.26434/chemrxiv.11831103.v2

Cited by 11 publications

(12 citation statements)

References 7 publications

(7 reference statements)

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“…The analysis of the trajectories showed that eluxadoline, which has been recently approved to be used in the treatment of Irritable Bowel Syndrome with diarrhea 92 Another compound identified in this study was diosmin, and like eluxadoline, it has been proposed as a candidate molecule in the treatment of SARS-CoV-2 in a couple of recent in silico studies 8, 93,94 . It is also important to emphasize that diosmin has been currently tested to be used in a combinatorial therapy with hesperidin for prophylaxis and treatment of COVID-19 95 .…”

Section: Clustering Of Trajectories Pertaining To Apo M-pro Revealed mentioning

confidence: 66%

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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Section: Clustering Of Trajectories Pertaining To Apo M-pro Revealed mentioning

confidence: 66%

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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“…The close similarity of the replication mechanism in the Hepatitis C virus and SARS-CoV-2 makes it an interesting therapeutic option for drug development. Recently, it was reported to interact with 3C like protease (3CLpro) of COVID-19 27 . Flavin adenine dinucleotide also depicted to have binding energy to be higher than the threshold (Figure 3 and Supplementary Information, Table S4).…”

Section: Docking Analysis Revealed the Interaction Of Top Hits With Tmentioning

confidence: 99%

Potential Drugs Targeting Nsp16 Protein May Corroborates a Promising Approach to Combat SARSCoV-2 Virus

Shankar¹,

Jain²,

Majee³

et al. 2020

Preprint

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The recent ongoing pandemic caused by SARS-CoV-2 continues to impose devastating impacts and is accountable for the loss of more than 250,000 human lives within a short span of four months. This urges immediate therapeutic measures to control the impact of this disease. One of the most conserved and potentially druggable sites is the Nsp16 active site that performs the 2’-O-methyltransferase activity and puts a 5’ cap on the viral RNA molecules. This allows them to mimic endogenous transcripts for the efficient translation of viral proteins and evasion of the immune response. Herein, we screened three libraries of compounds (>5500) with chemical diversity to identify hits against Nsp16 active site of SARS-CoV-2. From each library a top hit was identified, namely Velpatasvir from the FDA compounds; JFD00244 from the LOPAC library and compound 6 from the SAM based analog library. Interestingly, all three hits showed higher affinity than the positive controls. Velpatasvir is a known anti-viral drug used against Hepatitis C virus, and JFD00244 is a SIRT2 inhibitor. 100ns molecular simulation studies showed all three molecules to have stable and energetically favourable interactions with the active site of Nsp16. In summary, this investigation identified three potential drug candidates that are predicted to be potent Nsp16 inhibitors and could be pursued further in cell-based studies.

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“…Repurposing drugs is a much quicker endeavor than discovering new ones since their chemical optimization, toxicology profiling, clinical trials and bulk manufacturing are already in place [1]. Several research groups have already proposed possible candidates for testing [2][3][4][5][6][7]. The results of this testing could provide a spectrum of outcomes -ranging from a compound that show high promise for use in patient treatment to very little activity.…”

Section: Introductionmentioning

confidence: 99%

Conformations and Three-Dimensional Structures of Selected SARS-CoV-2 Drug Candidates

Heiden¹

2020

Preprint

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Quantum mechanical theories are used to search and optimized the conformations of proposed small molecule candidates for treatment of SARS-CoV-2. These candidate compounds are taken from what is reported in the news and in other pre-peer-reviewed literature (e.g. ChemRxiv, bioRxiv). The goal herein is to provided predicted structures and relative conformational stabilities for selected drug and ligand candidates, in the hopes that other research groups can make use of them for developing a treatment. Initial exploration for conformations are performed at the HF/6-31G(d)//HF/6-31G(d) theory level, which are then further optimized at more rigorous theory levels (e.g. B97-D3BJ/cc-pVTZ//B97-D3BJ/cc-pVTZ). The resulting structures are made available via GitHub.

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Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like Protease (3CLpro) Structure: Virtual Screening Reveals Velpatasvir, Ledipasvir, and Other Drug Repurposing Candidates

Cited by 11 publications

References 7 publications

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

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

Potential Drugs Targeting Nsp16 Protein May Corroborates a Promising Approach to Combat SARSCoV-2 Virus

Conformations and Three-Dimensional Structures of Selected SARS-CoV-2 Drug Candidates

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