Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An <i>In Silico</i> Study

Campos, Luana Janaína de; Palermo, Nicholas Y.; Conda‐Sheridan, Martin

doi:10.1021/acs.jpcb.1c02398

Cited by 16 publications

(19 citation statements)

References 82 publications

(199 reference statements)

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“… 62 Interestingly, stapled peptides have also been designed that target the RBD of the SARS-CoV-2, which upon analysis through MD simulations and binding free energy calculations has been shown to bind with a potency that is similar to that of experimentally proven peptide inhibitors. 63 …”

Section: Drug Design and Discoverymentioning

confidence: 99%

“…A similar work studied the effect of small molecules SSAA09E2 and Nilotinib on the ACE2-RBD interface through MD simulations and found that they intervene with hydrogen bonds at the interface and hence the flexibility of the proteins . Interestingly, stapled peptides have also been designed that target the RBD of the SARS-CoV-2, which upon analysis through MD simulations and binding free energy calculations has been shown to bind with a potency that is similar to that of experimentally proven peptide inhibitors …”

Section: Drug Design and Discoverymentioning

confidence: 99%

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Accelerating COVID-19 Research Using Molecular Dynamics Simulation

2021

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The COVID-19 pandemic has emerged as a global medico-socio-economic disaster. Given the lack of effective therapeutics against SARS-CoV-2, scientists are racing to disseminate suggestions for rapidly deployable therapeutic options, including drug repurposing and repositioning strategies. Molecular dynamics (MD) simulations have provided the opportunity to make rational scientific breakthroughs in a time of crisis. Advancements in these technologies in recent years have become an indispensable tool for scientists studying protein structure, function, dynamics, interactions, and drug discovery. Integrating the structural data obtained from high-resolution methods with MD simulations has helped in comprehending the process of infection and pathogenesis, as well as the SARS-CoV-2 maturation in host cells, in a short duration of time. It has also guided us to identify and prioritize drug targets and new chemical entities, and to repurpose drugs. Here, we discuss how MD simulation has been explored by the scientific community to accelerate and guide translational research on SARS-CoV-2 in the past year. We have also considered future research directions for researchers, where MD simulations can help fill the existing gaps in COVID-19 research.

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Section: Drug Design and Discoverymentioning

confidence: 99%

Section: Drug Design and Discoverymentioning

confidence: 99%

Accelerating COVID-19 Research Using Molecular Dynamics Simulation

2021

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“…The MM-GBSA binding free energy was estimated according to the formula: ΔGbind = Gcomplex – Greceptor – Gligand, where ΔGbind is the binding free energy and Gcomplex, Greceptor, and Gligand are the free energies of the complex, receptor, and ligand, respectively. MM-GBSA values were obtained from the script of thermal MM-GBSA provided by Schrödinger ( https://www.schrodinger.com/scriptcenter ) and were used to calculate the ΔGbind for the protein–ligand complexes [ 44 , 45 ].…”

Section: Methodsmentioning

confidence: 99%

Antiviral phytocompounds “ellagic acid” and “(+)-sesamin” of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected billions and has killed millions to date. Studies are being carried out to find therapeutic molecules that can potentially inhibit the replication of SARS-CoV-2. 3-chymotrypsin-like protease (3CL pro) involved in the polyprotein cleavage process is believed to be the key target for viral replication, and hence is an attractive target for the discovery of antiviral molecules. In the present study, we aimed to identify natural phytocompounds from Bridelia retusa as potential inhibitors of SARS-CoV-2 3CL pro (PDB ID: 6M2N) using in silico techniques. Molecular docking studies conducted with three different tools in triplicates revealed that ellagic acid (BR6) and (+)-sesamin (BR13) has better binding affinity than the co-crystal inhibitor “3WL” of 6M2N. BR6 and BR13 were found to have a high LD 50 value with good bioavailability. 3WL, BR6, and BR13 bind to the same active binding site and interacted with the HIS41-CYS145 catalytic dyad including other crucial amino acids. Molecular dynamics simulation studies revealed stability of protein–ligand complexes as evidenced from root-mean-square deviations, root-mean-square fluctuations (RMSF), protein secondary structure elements, ligand-RMSF, protein–ligand contacts, ligand torsions, and ligand properties. BR6 (−22.3064 kcal/mol) and BR13 (−19.1274 kcal/mol) showed a low binding free energy value. The Bayesian statistical model revealed BR6 and BR13 as better protease inhibitors than 3WL. Moreover, BR6 and BR13 had already been reported to elicit antiviral activities. Therefore, we conclude that ellagic acid and (+)-sesamin as natural antiviral phytocompounds with inhibitory potential against SARS-CoV-2 3CL pro. Supplementary information The online version contains supplementary material available at 10.1007/s11224-022-01959-3.

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“…De Campos et al [ 36 ] employed rational structure‐based design to propose 22‐mer stapled peptides using the structure of the hACE2 Helix 1, as a template. In this in silico approach, the researchers used different types of molecular configurations to construct the chemical linkers: lactam bridge, double lactam bridge, and alkene link (Figure 4 ).…”

Section: Stapled Peptides As Inhibitors Of Host Cell Entry By Sars‐co...mentioning

confidence: 99%

Stapled peptides as potential inhibitors of SARS‐CoV‐2 binding to the hACE2 receptor

Tzotzos

2022

Journal of Peptide Science

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Stapled peptides are synthetic peptidomimetics of bioactive sites in folded proteins which carry chemical links, introduced during peptide synthesis, designed to retain the secondary structure in the native protein molecule. Stapled peptides have been investigated as potential modulators of protein–protein interactions for over two decades. The potential use of stapled peptides as inhibitors of viral entry, and therefore as antiviral therapeutics, has been established for several important viruses causing disease in humans, such as the human immunodeficiency virus type 1 (HIV‐1), respiratory syncytial virus (RSV), and Middle East Respiratory Syndrome (MERS) coronavirus. Several independent research initiatives have investigated the inhibitory effect of stapled peptides on binding of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative agent of COVID‐19, to its receptor, angiotensin‐converting‐enzyme 2 (ACE2). These stapled peptides, which mimic Helix 1 of the human ACE2 receptor, have demonstrated mixed ability to prevent infection with SARS‐CoV‐2 in cell‐based studies.

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Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An In Silico Study

Cited by 16 publications

References 82 publications

Accelerating COVID-19 Research Using Molecular Dynamics Simulation

Accelerating COVID-19 Research Using Molecular Dynamics Simulation

Antiviral phytocompounds “ellagic acid” and “(+)-sesamin” of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction

Stapled peptides as potential inhibitors of SARS‐CoV‐2 binding to the hACE2 receptor

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