scholarly journals Repositioning of Ligands That Target the Spike Glycoprotein as Potential Drugs for SARS-CoV-2 in an In Silico Study

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5615
Author(s):  
Gema Lizbeth Ramírez-Salinas ◽  
Marlet Martínez-Archundia ◽  
José Correa-Basurto ◽  
Jazmín García-Machorro
Keyword(s):  
Amino Acids ◽  
Conformational Changes ◽  
Viral Entry ◽  
Drug Repositioning ◽  
Specific Treatment ◽  
Binding Motif ◽  
Spike Glycoprotein ◽  
Pharmacological Agents ◽  
Docking Simulations ◽  
Approved Drugs

The worldwide health emergency of the SARS-CoV-2 pandemic and the absence of a specific treatment for this new coronavirus have led to the use of computational strategies (drug repositioning) to search for treatments. The aim of this work is to identify FDA (Food and Drug Administration)-approved drugs with the potential for binding to the spike structural glycoprotein at the hinge site, receptor binding motif (RBM), and fusion peptide (FP) using molecular docking simulations. Drugs that bind to amino acids are crucial for conformational changes, receptor recognition, and fusion of the viral membrane with the cell membrane. The results revealed some drugs that bind to hinge site amino acids (varenicline, or steroids such as betamethasone while other drugs bind to crucial amino acids in the RBM (naldemedine, atovaquone, cefotetan) or FP (azilsartan, maraviroc, and difluprednate); saquinavir binds both the RBM and the FP. Therefore, these drugs could inhibit spike glycoprotein and prevent viral entry as possible anti-COVID-19 drugs. Several drugs are in clinical studies; by focusing on other pharmacological agents (candesartan, atovaquone, losartan, maviroc and ritonavir) in this work we propose an additional target: the spike glycoprotein. These results can impact the proposed use of treatments that inhibit the first steps of the virus replication cycle.

scholarly journals Repositioning of ligands that target spike glycoprotein as potential drugs against SARS-CoV-2

2020 ◽  
Author(s):  
Gema Lizbeth Ramírez-Salinas ◽  
Marlet Martínez-Archundia ◽  
José Correa-Basurto ◽  
Jazmín García-Machorro
Keyword(s):  
Amino Acids ◽  
Viral Entry ◽  
Drug Repositioning ◽  
Specific Treatment ◽  
Binding Motif ◽  
Spike Glycoprotein ◽  
Docking Simulations ◽  
Approved Drugs ◽  
Virus Replication Cycle ◽  
Fda Approved Drugs

Abstract The worldwide health emergency of the SARS-CoV-2 pandemic and the absence of a specific treatment for this new coronavirus have led to the use of computational strategies (drug repositioning) to search for treatments. The aim of this work is to identify FDA-approved drugs with the potential for binding to the spike structural glycoprotein at the hinge site, receptor binding motif (RBM), and fusion peptide (FP) using molecular docking simulations. It was identified drugs that binding to amino acids crucial for down to up conformational change, receptor recognition, and fusion of the viral membrane with the cell membrane. Results show some drugs that bind to hinge site amino acids (Varenicline, or even steroids as Betamethasone) while other drugs bind to crucial amino acids for RBM (Naldemedine, Atovaquone, Cefotetan) or FP (Edarbi, Maraviroc, Difluprednate); and highlights the Saquinavir that binds both the RBM and the FP. Therefore, these drugs could inhibit spike glycoprotein and prevent viral entry (possible anti-COVID-19 drugs). Several drugs are in clinical studies; focused on another pharmacological target (candesartan, Atovaquone, Losartan, Maviroc and Ritonavir) in this work we propose an additional target, the spike glycoprotein. These results can impact in the proposal of treatments that can inhibit the first steps virus replication cycle.

scholarly journals The key amino acids of E protein involved in early flavivirus infection: viral entry

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tao Hu ◽  
Zhen Wu ◽  
Shaoxiong Wu ◽  
Shun Chen ◽  
Anchun Cheng
Keyword(s):  
Amino Acids ◽  
Conformational Changes ◽  
Viral Entry ◽  
Envelope Protein ◽  
Cell Attachment ◽  
Envelope Proteins ◽  
Infection Process ◽  
Early Infection ◽  
Protein Amino Acids ◽  
Α Helix

AbstractFlaviviruses are enveloped viruses that infect multiple hosts. Envelope proteins are the outermost proteins in the structure of flaviviruses and mediate viral infection. Studies indicate that flaviviruses mainly use envelope proteins to bind to cell attachment receptors and endocytic receptors for the entry step. Here, we present current findings regarding key envelope protein amino acids that participate in the flavivirus early infection process. Among these sites, most are located in special positions of the protein structure, such as the α-helix in the stem region and the hinge region between domains I and II, motifs that potentially affect the interaction between different domains. Some of these sites are located in positions involved in conformational changes in envelope proteins. In summary, we summarize and discuss the key envelope protein residues that affect the entry process of flaviviruses, including the process of their discovery and the mechanisms that affect early infection.

scholarly journals An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

2020 ◽  
Author(s):  
Alfonso Trezza ◽  
Daniele Iovinelli ◽  
Filippo Prischi ◽  
Annalisa Santucci ◽  
Ottavia Spiga
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Docking Simulations ◽  
Approved Drugs

Abstract The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Nilotinib and Imatinib bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.

scholarly journals Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

2015 ◽  
Vol 112 (7) ◽  
pp. 2034-2039 ◽  
Author(s):  
Xiancheng Zeng ◽  
Suchetana Mukhopadhyay ◽  
Charles L. Brooks
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Viral Entry ◽  
Drug Targets ◽  
Viral Infections ◽  
Driving Forces ◽  
Specific Treatment ◽  
Icosahedral Symmetry ◽  
Endosomal Membranes ◽  
Ph Dependent

Alphavirus envelope proteins, organized as trimers of E2–E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections.

scholarly journals Structural and functional modelling of SARS-CoV-2 entry in animal models

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Greg N. Brooke ◽  
Filippo Prischi
Keyword(s):  
Animal Models ◽  
Protein Interaction ◽  
Viral Entry ◽  
High Specificity ◽  
Binding Mode ◽  
Transgenic Animal ◽  
Spike Protein ◽  
Binding Modes ◽  
Spike Glycoprotein ◽  
Docking Simulations

Abstract SARS-CoV-2 is the novel coronavirus responsible for the outbreak of COVID-19, a disease that has spread to over 100 countries and, as of the 26th July 2020, has infected over 16 million people. Despite the urgent need to find effective therapeutics, research on SARS-CoV-2 has been affected by a lack of suitable animal models. To facilitate the development of medical approaches and novel treatments, we compared the ACE2 receptor, and TMPRSS2 and Furin proteases usage of the SARS-CoV-2 Spike glycoprotein in human and in a panel of animal models, i.e. guinea pig, dog, cat, rat, rabbit, ferret, mouse, hamster and macaque. Here we showed that ACE2, but not TMPRSS2 or Furin, has a higher level of sequence variability in the Spike protein interaction surface, which greatly influences Spike protein binding mode. Using molecular docking simulations we compared the SARS-CoV and SARS-CoV-2 Spike proteins in complex with the ACE2 receptor and showed that the SARS-CoV-2 Spike glycoprotein is compatible to bind the human ACE2 with high specificity. In contrast, TMPRSS2 and Furin are sufficiently similar in the considered hosts not to drive susceptibility differences. Computational analysis of binding modes and protein contacts indicates that macaque, ferrets and hamster are the most suitable models for the study of inhibitory antibodies and small molecules targeting the SARS-CoV-2 Spike protein interaction with ACE2. Since TMPRSS2 and Furin are similar across species, our data also suggest that transgenic animal models expressing human ACE2, such as the hACE2 transgenic mouse, are also likely to be useful models for studies investigating viral entry.

scholarly journals An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

2020 ◽  
Author(s):  
Alfonso Trezza ◽  
Daniele Iovinelli ◽  
Filippo Prischi ◽  
Annalisa Santucci ◽  
Ottavia Spiga
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Docking Simulations ◽  
Approved Drugs

Abstract The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.Authors Alfonso Trezza and Daniele Iovinelli contributed equally to this work.

Identification of therapeutic target in S2 domain of SARS nCov-2 Spike glycoprotein: Key to design and discover drug candidates for inhibition of viral entry into host cell

2020 ◽  
Vol 19 (07) ◽  
pp. 2050028
Author(s):  
Gururaj Somadi ◽  
Sree Kanth Sivan
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Therapeutic Target ◽  
Structural Changes ◽  
Data Bank ◽  
Heptad Repeat ◽  
Spike Glycoprotein ◽  
Novel Coronavirus ◽  
Approved Drugs

Humanity is facing a grieve danger of coronavirus disease-19 caused by severe acute respiratory syndrome novel coronavirus-2 (SARS nCov-2). There is an urgent need of therapeutics that can help in overcoming this global pandemic. Identifying novel therapeutic target and screening already approved drug is a faster approach in this situation. Spike glycoprotein (Sgp) of SARS nCoV-2 is potentials target where in researchers have targeted receptor binding domain (RBD) of S1 domain. The S2 domain of Sgp also plays a pivotal role in viral entry, but the mechanism is less understood. We analyzed the structure of Sgp S2 domain in pre-fusion state and Heptad repeat region in its post-fusion state available from protein data bank. Sgp shows three major regions in S2 domain, the fusion peptide (FP), heptad repeat 1 (HR1) and central helical (CH) region. The HR1 region undergoes structural changes by flipping approximately 180∘ and coil up to form a rod like structure during fusion process implying its role in viral entry into the host cell. This structural change in S2 domain helices is crucial step, if this process is hindered by targeting the HR1 and CH region then the progression of virus can be stopped. Possible binding cavity was identified near the HR1 and CH region in S2 domain and docking-based virtual screening of FDA approved drugs was performed. Promising candidates like Troxerutin, Thymopentin and Daclatasvir can be used as therapeutics provided an immediate in-vitro and clinical studies are carried out by research groups.

scholarly journals Cryo-EM analysis of the HCoV-229E spike glycoprotein reveals dynamic prefusion conformational changes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiyong Song ◽  
Yuejun Shi ◽  
Wei Ding ◽  
Tongxin Niu ◽  
Limeng Sun ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Viral Entry ◽  
Therapeutic Antibody ◽  
Host Cells ◽  
Structural Comparison ◽  
Spike Glycoprotein ◽  
Closed Conformation ◽  
Open Conformation ◽  
Receptor Recognition ◽  
Antibody Design

AbstractCoronaviruses spike (S) glycoproteins mediate viral entry into host cells by binding to host receptors. However, how the S1 subunit undergoes conformational changes for receptor recognition has not been elucidated in Alphacoronavirus. Here, we report the cryo-EM structures of the HCoV-229E S trimer in prefusion state with two conformations. The activated conformation may pose the potential exposure of the S1-RBDs by decreasing of the interaction area between the S1-RBDs and the surrounding S1-NTDs and S1-RBDs compared to the closed conformation. Furthermore, structural comparison of our structures with the previously reported HCoV-229E S structure showed that the S trimers trended to open the S2 subunit from the closed conformation to open conformation, which could promote the transition from pre- to postfusion. Our results provide insights into the mechanisms involved in S glycoprotein-mediated Alphacoronavirus entry and have implications for vaccine and therapeutic antibody design.

Is the Rigidity of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity and Pathogenesis?

2020 ◽  
Author(s):  
Angelo Spinello ◽  
Andrea Saltalamacchia ◽  
Alessandra Magistrato
Keyword(s):  
Health Economic ◽  
Global Health ◽  
Receptor Binding ◽  
Binding Motif ◽  
Spike Glycoprotein ◽  
High Affinity ◽  
Global Pandemic ◽  
Medical Countermeasures ◽  
High Infectivity ◽  
Human Receptor

<p>The latest outbreak of a new pathogenic coronavirus (SARS-CoV-2) is provoking a global health, economic and societal crisis. All-atom simulations enabled us to uncover the key molecular traits underlying the high affinity of SARS-CoV-2 spike glycoprotein towards its human receptor, providing a rationale to its high infectivity. Harnessing this knowledge can boost developing effective medical countermeasures to fight the current global pandemic.</p>

Repositioning Drugs for Rare Immune Diseases: Hopes and Challenges for a Precision Medicine

2018 ◽  
Vol 25 (24) ◽  
pp. 2764-2782 ◽  
Author(s):  
Erica Valencic ◽  
Alenka Smid ◽  
Ziga Jakopin ◽  
Alberto Tommasini ◽  
Irena Mlinaric-Rascan
Keyword(s):  
Precision Medicine ◽  
Rare Diseases ◽  
Business Models ◽  
Drug Repositioning ◽  
Drug Action ◽  
Primary Immunodeficiency Diseases ◽  
Computational Sciences ◽  
Approved Drugs ◽  
Molecular Mode ◽  
Viable Business

Human primary immunodeficiency diseases (PIDs) are a large group of rare diseases and are characterized by a great genetic and phenotypic heterogeneity. A large subset of PIDs is genetically defined, which has a crucial impact for the understanding of the molecular basis of disease and the development of precision medicine. <p> Discovery and development of new therapies for rare diseases has long been de-privileged due to the length and cost of the processes involved. Interest has increased due to stimulatory regulatory and supportive reimbursement environments enabling viable business models. <p> Advancements in biomedical and computational sciences enable the development of rational, designed approaches for identification of novel indications of already approved drugs allowing faster delivery of new medicines. Drug repositioning is based either on clinical analogies of diseases or on understanding of the molecular mode of drug action and mechanisms of the disease. All of these are the basis for the development of precision medicine.

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