Repurposing of approved drug molecules for viral infectious diseases: a molecular modelling approach

Kumar, Nandan; Sarma, Himakshi; Sastry, G. Narahari

doi:10.1080/07391102.2021.1905558

Cited by 12 publications

(8 citation statements)

References 110 publications

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“…BepiPred-2.0 essentially works with the random forest algorithm with a reasonably high accuracy score. 18 Then, by default, parameters were set for the analysis. The 20mer amino acid sequences that were commonly predicted from both servers were considered the predicted epitopes.…”

Section: Computationalmentioning

confidence: 99%

Glycoprotein attachment with host cell surface receptor ephrin B2 and B3 in mediating entry of nipah and hendra virus: a computational investigation

2022

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Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic paramyxovirus which belongs to Henipavirus family, causes severe respiratory disease, and may lead to fatal encephalitis infections in humans. NiV and HeV glycoproteins (G) bind to the highly conserved human ephrin-B2 and B3 (EFNB2 & EFNB3) cell surface proteins to mediate the viral entry. In this study, various molecular modelling approaches were employed to understand protein-protein interaction (PPI) of NiV and HeV glycoprotein (84% sequence similarity) with Human EFN (B2 and B3) to investigate the molecular mechanism of interaction at atomic level. Our computational study emphasized the PPI profile of both the viral glycoproteins with EFN (B2 and B3) in terms of non-bonded contacts, H-bonds, salt bridges, and identification of interface hotspot residues which play a critical role in the formation of complexes that mediate viral fusion and entry into the host cell. According to the reports, EFNB2 is considered to be more actively involved in the attachment with the NiV and HeV glycoprotein; interestingly the current computational study has displayed more conformational stability in HeV/NiV glycoprotein with EFNB2 complex with relatively high binding energy as compared to EFNB3. During the MD simulation, the number of H-bond formations was observed to be less in the case of EFNB3 complexes, which may be the possible reason for less conformational stability in the EFNB3 complexes. The current detailed interaction study on the PPI may put a path forward in designing peptide inhibitors to obstruct the interaction of viral glycoproteins with host proteins, thereby inhibiting viral entry. Graphical abstract The viral attachment and fusion of Nipah and Hendra virus was explored through the interaction between viral glycoprotein and the host cell surface ephrin protein. The MD simulation results displayed more stability in Nipah and Hendra glycoprotein with EFNB2 as compared to EFNB3. The residue Glu533 in the central cavity of HeV/NiV glycoprotein protein identified as the potential hotspot in binding with the G-H loop of EFNB2. Supplementary Information The online version contains supplementary material available at 10.1007/s12039-022-02110-9.

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Section: Computationalmentioning

confidence: 99%

Glycoprotein attachment with host cell surface receptor ephrin B2 and B3 in mediating entry of nipah and hendra virus: a computational investigation

2022

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“…As a response to the COVID-19 pandemic, several studies have utilized various molecular modeling approaches for repurposing pre-existing drugs. 38 – 41 There are a few repurposed drugs available in the market for COVID-19 treatment, however, several limitations have been observed with the existing drugs. 9 , 42 – 44 To examine the relevance of the selected seven targets, a docking study has been performed on the 15 clinically repurposed drugs that were extensively employed for the COVID-19 treatment (Figure 2 and Figure S1, SI).…”

Section: Introductionmentioning

confidence: 99%

Applying polypharmacology approach for drug repurposing for SARS-CoV2

et al. 2022

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Exploring the new therapeutic indications of known drugs for treating COVID-19, popularly known as drug repurposing, is emerging as a pragmatic approach especially owing to the mounting pressure to control the pandemic. Targeting multiple targets with a single drug by employing drug repurposing known as the polypharmacology approach may be an optimised strategy for the development of effective therapeutics. In this study, virtual screening has been carried out on seven popular SARS-CoV-2 targets (3CL pro , PL pro , RdRp (NSP12), NSP13, NSP14, NSP15, and NSP16). A total of 4015 approved drugs were screened against these targets. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected based on the docking score, ability to interact with four or more targets and having a reasonably good number of interactions with key residues in the targets. The MD simulations and MM-PBSA studies showed reasonable stability of protein-drug complexes and sustainability of key interactions between the drugs with their respective targets throughout the course of MD simulations. The identified four drug molecules were also compared with the known drugs namely elbasvir and nafamostat. While the study has provided a detailed account of the chosen protein-drug complexes, it has explored the nature of seven important targets of SARS-CoV-2 by evaluating the protein-drug complexation process in great detail. Graphical abstract Drug repurposing strategy against SARS-CoV2 drug targets. Computational analysis was performed to identify repurposable approved drug candidates against SARS-CoV2 using approaches such as virtual screening, molecular dynamics simulation and MM-PBSA calculations. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected as potential candidates. Supplementary Information The online version contains supplementary material available at 10.1007/s12039-022-02046-0.

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“…Various computational approaches have been employed to decipher the active site and hotspot residues of macromolecules such as proteins and DNA for drug targeting. 63 − 65 While targeting the PPI interface remains an issue, in designing and discovery of small molecule inhibitors or modulators because the PPI interface are highly dynamic in nature. Therefore, various attempts have been made by different groups to understand the molecular mechanism of PPI at the atomic level through MD simulation studies to predict the hotspot residues for drug design.…”

Section: Introductionmentioning

confidence: 99%

“…The PDBsum server was used to analyze the PPI profile, and hotspot residues at the NSP14–NSP10 interface were identified using different computational approaches implemented in web servers including the KFC2, DrugScore PPI , and Robetta servers along with per-residue energy contribution analysis. , A single method may not give a significant result; thus, these methods were considered for accuracy improvement for hotspot identification. Various computational approaches have been employed to decipher the active site and hotspot residues of macromolecules such as proteins and DNA for drug targeting. − While targeting the PPI interface remains an issue, in designing and discovery of small molecule inhibitors or modulators because the PPI interface are highly dynamic in nature. Therefore, various attempts have been made by different groups to understand the molecular mechanism of PPI at the atomic level through MD simulation studies to predict the hotspot residues for drug design. ,− …”

Section: Introductionmentioning

confidence: 99%

A Computational Study on the Interaction of NSP10 and NSP14: Unraveling the RNA Synthesis Proofreading Mechanism in SARS-CoV-2, SARS-CoV, and MERS-CoV

Sarma

Sastry

2022

ACS Omega

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The interaction of exoribonuclease (ExoN) nonstructural protein (NSP14) with NSP10 co-factors is crucial for high-fidelity proofreading activity of coronavirus replication and transcription. Proofreading function is critical for maintaining the large genomes to ensure replication proficiency; therefore, while maintaining the viral replication fitness, quick resistance has been reported to the nucleotide analogue (NA) drugs. Therefore, targeting the NSP14 and NSP10 interacting interface with small molecules or peptides could be a better strategy to obstruct replication processes of coronaviruses (CoVs). A comparative study on the binding mechanism of NSP10 with the NSP14 ExoN domain of SARS-CoV-2, SARS-CoV, MERS-CoV, and four SARS-CoV-2 NSP14 mutant complexes has been carried out. Protein–protein interaction (PPI) dynamics, per-residue binding free energy (BFE) analyses, and the identification of interface hotspot residues have been studied using molecular dynamics simulations and various computational tools. The BFE of the SARS-CoV NSP14–NSP10 complex was higher when compared to novel SARS-CoV-2 and MERS. However, SARS-CoV-2 NSP14 mutant systems display a higher BFE as compared to the wild type (WT) but lower than SARS-CoV and MERS. Despite the high BFE, the SARS-CoV NSP14–NSP10 complex appears to be structurally more flexible in many regions especially the catalytic site, which is not seen in SARS-CoV-2 and its mutant or MERS complexes. The significantly high residue energy contribution of key interface residues and hotspots reveals that the high binding energy between NSP14 and NSP10 may enhance the functional activity of the proofreading complex, as the NSP10–NSP14 interaction is essential in maintaining the stability of the ExoN domain for the replicative fitness of CoVs. The factors discussed for SARS-CoV-2 complexes may be responsible for NSP14 ExoN having a high replication proficiency, significantly leading to the evolution of new variants of SARS-CoV-2. The NSP14 residues V66, T69, D126, and I201and eight residues of NSP10 (L16, F19, V21, V42, M44, H80, K93, and F96) are identified as common hotspots. Overall, the interface area, hotspot locations, bonded/nonbonded contacts, and energies between NSP14 and NSP10 may pave a way in designing potential inhibitors to disrupt NSP14–NSP10 interactions of CoVs especially SARS-CoV-2.

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Repurposing of approved drug molecules for viral infectious diseases: a molecular modelling approach

Cited by 12 publications

References 110 publications

Glycoprotein attachment with host cell surface receptor ephrin B2 and B3 in mediating entry of nipah and hendra virus: a computational investigation

Glycoprotein attachment with host cell surface receptor ephrin B2 and B3 in mediating entry of nipah and hendra virus: a computational investigation

Applying polypharmacology approach for drug repurposing for SARS-CoV2

A Computational Study on the Interaction of NSP10 and NSP14: Unraveling the RNA Synthesis Proofreading Mechanism in SARS-CoV-2, SARS-CoV, and MERS-CoV

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