Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase

Mirza, Muhammad Usman; Froeyen, Matheus

doi:10.1016/j.jpha.2020.04.008

Cited by 236 publications

(229 citation statements)

References 46 publications

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“…NSP13 adopts a triangular pyramid shape structure with 5 domains in SARS-CoV 48 and in modeled SARS-CoV-2 molecules. 49 Three Rec-A domain structures, 1A and 2A and 2B form a triangular base for the N-terminal Zn binding domain (ZBD) and the stalk domain. The triangular base forms a nucleic acid binding channel with 1A crucially participating in unwinding, in which 1A tightens the grasp on the nucleic acid while 2A loosens the grip in each translocation unwinding step.…”

Section: Discussionmentioning

confidence: 99%

New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release

Tomaszewski

DeVries

Dong

et al. 2020

Evol Bioinform Online

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The massive worldwide spread of the SARS-CoV-2 virus is fueling the COVID-19 pandemic. Since the first whole-genome sequence was published in January 2020, a growing database of tens of thousands of viral genomes has been constructed. This offers opportunities to study pathways of molecular change in the expanding viral population that can help identify molecular culprits of virulence and virus spread. Here we investigate the genomic accumulation of mutations at various time points of the early pandemic to identify changes in mutationally highly active genomic regions that are occurring worldwide. We used the Wuhan NC_045512.2 sequence as a reference and sampled 15 342 indexed sequences from GISAID, translating them into proteins and grouping them by month of deposition. The per-position amino acid frequencies and Shannon entropies of the coding sequences were calculated for each month, and a map of intrinsic disorder regions and binding sites was generated. The analysis revealed dominant variants, most of which were located in loop regions and on the surface of the proteins. Mutation entropy decreased between March and April of 2020 after steady increases at several sites, including the D614G mutation site of the spike (S) protein that was previously found associated with higher case fatality rates and at sites of the NSP12 polymerase and the NSP13 helicase proteins. Notable expanding mutations include R203K and G204R of the nucleocapsid (N) protein inter-domain linker region and G251V of the viroporin encoded by ORF3a between March and April. The regions spanning these mutations exhibited significant intrinsic disorder, which was enhanced and decreased by the N-protein and viroporin 3a protein mutations, respectively. These results predict an ongoing mutational shift from the spike and replication complex to other regions, especially to encoded molecules known to represent major β-interferon antagonists. The study provides valuable information for therapeutics and vaccine design, as well as insight into mutation tendencies that could facilitate preventive control.

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Section: Discussionmentioning

confidence: 99%

New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release

Tomaszewski

DeVries

Dong

et al. 2020

Evol Bioinform Online

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“…It exhibits 36 significant mutations in the phase 2, among which, 20 of them are common to both the phases (A18V, V49I, S74L, P78S, D204Y, G206C, V226L, H290Y, L297P, V348L, P364S, R392C, S468L, V479F, S485L, P504L, Y541C, V570L, M576I and T588I). The co-mutation P504L (nucleic acid binding channel, 2A domain) and Y541C (nucleic acid binding pocket, 2A domain) 37,38 occurs not only at the highest significance, but also, at a similar frequency in same countries (Figure 3). The USA is the highest bearer of this mutation followed by Australia along with a few incidences in 7 other countries in phase 2.…”

Section: Pdb Id: 6zct 7bq7)mentioning

confidence: 97%

“…The helicase NSP13 36 is of 601 amino acids long and comprises of zinc binding domain (residue numbers 1-99), stalk (100-149), 1B (150-260), 1A (261-441) and 2A (442-596) 37,38 domains. It exhibits 36 significant mutations in the phase 2, among which, 20 of them are common to both the phases (A18V, V49I, S74L, P78S, D204Y, G206C, V226L, H290Y, L297P, V348L, P364S, R392C, S468L, V479F, S485L, P504L, Y541C, V570L, M576I and T588I).…”

Section: Pdb Id: 6zct 7bq7)mentioning

confidence: 99%

Global variation in the SARS-CoV-2 proteome reveals the mutational hotspots in the drug and vaccine candidates

Patro

Sathyaseelan

Uttamrao

et al. 2020

Preprint

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To accelerate the drug and vaccine development against the severe acute respiratory syndrome virus 2 (SARS-CoV-2), a comparative analysis of SARS-CoV-2 proteome has been performed in two phases by considering manually curated 31389 whole genome sequences from 84 countries. Among the 9 mutations that occur at a high significance (T85I-NPS2, L37F-NSP6, P323L-NSP12, D614G-spike, Q57H-ORF3a, G251V-ORF3a, L84S-ORF8, R203K-nucleocapsid and G204R-nucleocapsid), R203K-nucleocapsid and G204R-nucleocapsid are co-occurring mutations and P323L-NSP12 and D614G-spike often appear simultaneously. Other notable variations that appear with a moderate to low significance are, M85-NSP1 deletion, D268-NSP2 deletion, 112 amino acids deletion in ORF8, a phenylalanine insertion amidst F34-F36 (NSP6) and several co-existing substitution/deletion (I559V & P585S in NSP2, P504L & Y541C in NSP13, G82 & H83 deletions in NSP1 and K141, S142 & F143 deletions in NSP2) mutations. P323L-NSP12, D614G-spike, L37F-NSP6, L84S-ORF8 and the sequences deficient of the high significant mutations has led to 4 major SARS-CoV-2 clades. The top 5 countries bearing all the high significant and majority of the moderate significant mutations are: USA, England, Wales, Australia and Scotland. Further, the majority of the significant mutations has evolved in the first phase and has already transmitted around the globe indicating the positive selection pressure. Among the 26 SARS-CoV-2 proteins, nucleocapsid protein, ORF3a, ORF8, RNA dependent RNA polymerase and spike exhibit a higher heterogeneity compared with the rest of the proteins. However, NSP9, NSP10, NSP8, the envelope protein and NSP4 are highly resistant to mutations and can be exploited for drug/vaccine development.

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“…There exist two kinds of proteins in SARS-Cov-2 proteome, the non structural and the structural proteins. The non structural proteins principally participate in the process of viral replication, whereas the structural proteins function in the progression of viral assembly and infection within the host 51 . Therefore, both classes of proteins should bear equal consideration while either developing a vaccine or a drug.…”

Section: Selection Of Antigenic Proteins Their Retrieval and Homologmentioning

confidence: 99%

Engineering a Multi Epitope Vaccine Against SARS-CoV-2 By Exploiting Its Non Structural and Structural Proteins

Rajput

Sharma

Kumari

et al. 2020

Preprint

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Abstract SARS-CoV-2, the causative agent behind the ongoing pandemic exhibits an enhanced potential for infection when compared to its related family members- the SARS-CoV and MERS-CoV; which have caused similar disease outbreaks in the past. The severity of the global health burden, increasing mortality rate and the emergent economic crisis urgently demands the development of next- generation vaccines. Amongst such emergent next generation vaccines are the multi-epitope subunit vaccines, which hold promise in combating deadly pathogens. In this study we have exploited immunoinformatics applications to delineate a vaccine candidate possessing multiple B and T cells epitopes utilizing the SARS-CoV-2 non structural and structural proteins. The antigenicity potential, safety, structural stability and the production feasibility of the designed construct was evaluated computationally. Furthermore, due to the known crucial interactions of human TLR-3 immune receptor with SARS-CoV, the vaccine construct was examined for its binding efficiency using molecular docking and molecular dynamics simulation studies, which resulted in strong and stable interactions. Finally, the immune simulation studies suggested an effective immune response on vaccine administration. Overall, the immunoinformatics analysis advocates that the purposed vaccine candidate is safe and immunogenic and therefore can be pushed as a lead for in vitro and in vivo investigations.

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Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase

Cited by 236 publications

References 46 publications

New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release

New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release

Global variation in the SARS-CoV-2 proteome reveals the mutational hotspots in the drug and vaccine candidates

Engineering a Multi Epitope Vaccine Against SARS-CoV-2 By Exploiting Its Non Structural and Structural Proteins

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