Molecular Modelling Reveals Eight Novel Druggable Binding Sites in SARS-CoV-2’s Spike Protein

Marion, Ilke Ugur; Marion, Antoine

doi:10.26434/chemrxiv.13292768.v2

Cited by 3 publications

(2 citation statements)

References 6 publications

(6 reference statements)

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“…This suggested linoleate and dexamethasone stabilized the locked S conformation, while cholesterol destabilized it by binding to another site in the hinge region [ 6 ]. Another study of eight putative binding sites on the S protein identified additional ligands that bind to the FABP and stabilize the closed conformation [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

Piplani

Singh

Petrovsky

et al. 2023

IJMS

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Drugs against novel targets are needed to treat COVID-19 patients, especially as SARS-CoV-2 is capable of rapid mutation. Structure-based de novo drug design and repurposing of drugs and natural products is a rational approach to discovering potentially effective therapies. These in silico simulations can quickly identify existing drugs with known safety profiles that can be repurposed for COVID-19 treatment. Here, we employ the newly identified spike protein free fatty acid binding pocket structure to identify repurposing candidates as potential SARS-CoV-2 therapies. Using a validated docking and molecular dynamics protocol effective at identifying repurposing candidates inhibiting other SARS-CoV-2 molecular targets, this study provides novel insights into the SARS-CoV-2 spike protein and its potential regulation by endogenous hormones and drugs. Some of the predicted repurposing candidates have already been demonstrated experimentally to inhibit SARS-CoV-2 activity, but most of the candidate drugs have yet to be tested for activity against the virus. We also elucidated a rationale for the effects of steroid and sex hormones and some vitamins on SARS-CoV-2 infection and COVID-19 recovery.

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Section: Introductionmentioning

confidence: 99%

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

Piplani

Singh

Petrovsky

et al. 2023

IJMS

View full text Add to dashboard Cite

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“…In other very interesting studies, the authors described druggability assessment for the SARS-CoV-2 proteome followed by docking of phytomolecules, the mapping of druggable binding pockets on the experimental structures of 15 SARS-CoV-2 proteins genetic variabilities, a web-based server for navigating possible interactions between SARS-CoV-2 and human proteins, and a web server that predicts the binding modes between SARS-CoV-2 proteins and ligands . In addition to annotated and systematic databases, numerous studies on SARS-CoV-2 potential drug candidate binding sites have been reported. − …”

Section: Introductionmentioning

confidence: 99%

CROMATIC: Cross-Relationship Map of Cavities from Coronaviruses

Siragusa

Menna

Buratta

et al. 2022

J. Chem. Inf. Model.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 disease, has rapidly imposed an urgent need to identify effective drug candidates. In this context, the high resolution and non-redundant beta-Coronavirus protein cavities database is pivotal to help virtual screening protocols. Furthermore, the cross-relationship among cavities can lead to highlighting multitarget therapy chances. Here, we first collect all protein cavities on SARS-CoV-2, SARS-CoV, and MERS-CoV X-ray structures, and then, we compute a similarity map by using molecular interaction fields (MIFs). All the results come together in CROMATIC (CROss-relationship MAp of CaviTIes from Coronaviruses). CROMATIC encloses both a comprehensive and a non-redundant version of the cavities collection and a similarity map revealing, on the one hand, cavities that are conserved among the three Coronaviruses and, on the other hand, unexpected similarities among cavities that can represent a key starting point for multitarget therapy strategies. Similarity analysis was also performed for the available structures of SARS-CoV-2 spike variants, linking sequence mutations to three-dimensional interaction alterations. The CROMATIC repository is freely available to the scientific community at .

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Repurposing of Four Drugs as Anti-SARS-CoV-2 Agents and Their Interactions with Protein Targets

et al. 2022

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Although there are existing vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), new COVID-19 cases are increasing due to low immunization coverage and the emergence of new variants. For this reason, new drugs to treat and prevent severe COVID-19 are needed. Here, we provide four different FDA-approved drugs against SARS-CoV-2 proteins involved in the entry and replication process, aiming to identify potential drugs to treat COVID-19. We use the main protease (Mpro), the spike glycoprotein (S protein), and RNA-dependent RNA polymerase (RdRp) as protein targets for anti- SARS-CoV-2 drugs. In our constructed database, we selected different drugs against each target (Mpro, S protein, and RdRp) based on their common interactions with relevant residues involved in viral entry at the host cell and replication. Furthermore, their stability inside the binding pocket, as well as their predicted binding-free energy, allow us to provide new insight into the possible drug repurposing of viomycin (interacting with Mpro) due to its interactions with key residues, such as Asn 143, Glu 166, and Gln 189 at the same time as hesperidin (interacting with the S protein) is interacting with residues Tyr 449, Ser 494, and Thr 500, keeping inside the predicted binding pocket, as well as interacting with residues in different variants of concern. Finally, we also suggest nystatin and elvitegravir (interacting with RdRp) as possible drugs due to their stability within the predicted pocket along the simulation and their interaction with key residues, such as Asp 760, Asp 761, and Asp 618. Altogether our results provide new knowledge about the possible mechanism of the inhibition of viomycin, hesperidin, elvitegravir, and nystatin to inhibit the viral life cycle of SARS-CoV-2 and some of its variants of concern (VOC). Additionally, some iodide-based contrast agents were also found to bind the S protein strongly, i.e., iohexol (−58.99 Kcal/mol), iotrolan (−76.19 Kcal/mol), and ioxilan (−62.37 Kcal/mol). Despite the information we report here as the possible strong interaction between these contrast agents and the SARS-CoV-2′s S protein, Mpro, and RdRp, we believe that further investigation, including chemical modifications in their structures, are needed for COVID-19 treatment.

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Molecular Modelling Reveals Eight Novel Druggable Binding Sites in SARS-CoV-2’s Spike Protein

Cited by 3 publications

References 6 publications

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

CROMATIC: Cross-Relationship Map of Cavities from Coronaviruses

Repurposing of Four Drugs as Anti-SARS-CoV-2 Agents and Their Interactions with Protein Targets

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