Therapeutically effective covalent spike protein inhibitors in treatment of SARS-CoV-2

Choudhary, Vikram; Gupta, Amisha; Sharma, Rajesh; Parmar, Hamendra Singh

doi:10.1007/s42485-021-00074-x

Cited by 9 publications

(9 citation statements)

References 133 publications

(170 reference statements)

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“…Electrophilic peptides that form an irreversible covalent bond with their target, even if have not been widely used in the past because of the difficulty in their molecular design, are now considered a potential therapeutic tool (Chitsike and Duerksen-Hughes 2021 ; Choudhary et al 2021 ; Tivon et al 2021 ). We assume that a portion (indicated by IS) of an inhibitor peptidomimetic I is characterized by its marked covalent capacity, while the rest of the molecule would maintain the property of giving the typical bonds.…”

Section: Strategies To Avoid the Binding Processmentioning

confidence: 99%

SARS-CoV-2 spike and ACE2 entanglement-like binding

Pregnolato

Zizzi

2023

Quantum Mach. Intell.

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We describe the binding between the glycoprotein Spike of SARS-CoV-2 and the human host cell receptor ACE2 as a quantum circuit, comprising the one-qubit Hadamard quantum logic gate performing the quantum superposition of the S 1 subunit of the Spike protein, and the two-qubit quantum logic gate CNOT, which performs maximum entanglement between the Spike-qubit S 1 and the ACE2 receptor protein. Also, we consider two strategies to prevent the binding process between the Spike-qubit S 1 and the ACE2 receptor. The first one is the use of competitive peptidomimetic inhibitors that can selectively bind to the receptor binding domain (RBD) of the Spike glycoprotein with much higher affinity than the cell surface receptor itself. These inhibitors are targeted to the CNOT quantum logic gate and will get maximally entangled with the S 1 qubit in place of the natural ACE2 receptor. The second one is to use covalent inhibitors, which will destroy S 1 by acting as a projective quantum measurement. Finally, the conjecture that S 1 is a quantum bio-robot is formulated.

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Section: Strategies To Avoid the Binding Processmentioning

confidence: 99%

SARS-CoV-2 spike and ACE2 entanglement-like binding

Pregnolato

Zizzi

2023

Quantum Mach. Intell.

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“…As a result, numerous compounds were developed as anti-SARS-CoV-2 agents and therapies or prevent the virus’s sequelae, have been studied in silico , in vitro , and in human clinical trials ( Ghareeb et al, 2021 ). Several molecular targets were utilized to develop novel chemicals to combat Coronaviruses such as virus spike ( Choudhary et al, 2021 ), main protease ( Mostafa et al, 2021 ), papain-like protease ( Delre et al, 2020 ; Mahmoud et al, 2021 ), helicase ( Gurung, 2020 ) and RNA-dependent RNA polymerase ( Molavi et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Antiviral drug discovery by targeting the SARS-CoV-2 polyprotein processing by inhibition of the main protease

Kandeel

Fayez

Kitade

et al. 2022

PeerJ

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The spread of SARS-CoV-2, the causative agent for COVID-19, has led to a global and deadly pandemic. To date, few drugs have been approved for treating SARS-CoV-2 infections. In this study, a structure-based approach was adopted using the SARS-CoV-2 main protease (Mpro) and a carefully selected dataset of 37,060 compounds comprising Mpro and antiviral protein-specific libraries. The compounds passed two-step docking filtration, starting with standard precision (SP) followed by extra precision (XP) runs. Fourteen compounds with the highest XP docking scores were examined by 20 ns molecular dynamics simulations (MDs). Based on backbone route mean square deviations (RMSD) and molecular mechanics/generalized Born surface area (MM/GBSA) binding energy, four drugs were selected for comprehensive MDs analysis at 100 ns. Results indicated that birinapant, atazanavir, and ritonavir potently bound and stabilized SARS-CoV-2 Mpro structure. Binding energies higher than −102 kcal/mol, RMSD values <0.22 nm, formation of several hydrogen bonds with Mpro, favourable electrostatic contributions, and low radii of gyration were among the estimated factors contributing to the strength of the binding of these three compounds with Mpro. The top two compounds, atazanavir and birinapant, were tested for their ability to prevent SARS-CoV-2 plaque formation. At 10 µM of birinapant concentration, antiviral tests against SARS-CoV-2 demonstrated a 37% reduction of virus multiplication. Antiviral assays demonstrated that birinapant has high anti-SARS-CoV-2 activity in the low micromolar range, with an IC50 value of 18 ± 3.6 µM. Therefore, birinapant is a candidate for further investigation to determine whether it is a feasible therapy option.

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“…In fact, SARS-CoV-2, like SARS-CoV, utilizes S1 domain, which comprising the receptor-binding domain (RBD) of S-protein, to initiate its attachment to the host cell through the binding of the human angiotensin-converting enzyme 2 (hACE2) receptor of the target cell. While, its entry in the host cell is mediated by the S2 subunit after a membrane fusion [12][13][14]. Thus, targeting this protein remains of highly important potential to generate novel drugs that block the entry of the virus inside the target cells.…”

Section: Introductionmentioning

confidence: 99%

Towards potent Covid-19 spike protein inhibitors and catecholase activity agents: Synthesis, ADME-Tox analysis and molecular docking of new 1,2,4- triazole-based molecules

Zerrouki¹,

Abrigach²,

Taleb

et al. 2022

Preprint

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The discovery of new efficiency therapeutic agents that can block the adhesion of the transmembrane glycoprotein Spike (S-protein) to the human angiotensin-converting enzyme 2 (hACE2) receptor remains one of the most investigated strategies to fight against Covid-19 pandemic. In this context, new triazole derivatives have been synthesized through condensation reactions between (1H-1, 2, 4-triazol-1-yl)methanol and different secondary amines. Their chemical scaffolds were well illuminated by 1H/ 13C/ COSY/ HSQC NMR, FT-IR and mass spectroscopies. In silico investigations have been carried out. ADME-Tox screening revealed that the prepared compounds could serve as excellent oral candidate drugs with optimal pharmacokinetic proprieties and toxicological profiles. Molecular docking simulations against the isolated S-RBD protein and SARS-CoV-2-RBD- hACE2 complex showed that our compounds could form important hydrogen, hydrophobic and electrostatic interactions with some key residues that ensure the binding of the S-protein to its hACE2 receptor making them good candidate agents that can block or prevent the entry of SARS-CoV-2 virus in the host cell. Additionally, catecholase activity of the tridentate ligands have been studied. The obtained findings demonstrated that a systematic variation of the ligand substituent and metallic salts types, significantly influences the interaction of the in situ complexes with catechol and hence the oxidase biomimetic catalytic activities. Complex L3/Cu(CH3COO)2 was found to exhibit the highest activity towards oxidation of catechol to its corresponding quinone with a rate of 2.44 𝜇mol.l−1.min−1.

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Therapeutically effective covalent spike protein inhibitors in treatment of SARS-CoV-2

Cited by 9 publications

References 133 publications

SARS-CoV-2 spike and ACE2 entanglement-like binding

SARS-CoV-2 spike and ACE2 entanglement-like binding

Antiviral drug discovery by targeting the SARS-CoV-2 polyprotein processing by inhibition of the main protease

Towards potent Covid-19 spike protein inhibitors and catecholase activity agents: Synthesis, ADME-Tox analysis and molecular docking of new 1,2,4- triazole-based molecules

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