The Main Protease of SARS COV-2 and Its Specific Inhibitors

Ghassemlou, Abdulrahman; Sefidbakht, Yahya; Rahmandoust, Moones

doi:10.1007/978-981-16-3108-5_4

Cited by 4 publications

(7 citation statements)

References 80 publications

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“…Each monomer of Mpro has 306 amino acid residues and contains three domains. It should be noted that Mpro is only active in the dimer mode, while its monomer mode is inactive 20 . In fact, the Mpro of SARS‐CoV‐2 has a close structural similarity to the SARS‐CoV Mpro.…”

Section: Introductionmentioning

confidence: 96%

“…It should be noted that Mpro is only active in the dimer mode, while its monomer mode is inactive. 20 In fact, the Mpro of SARS-CoV-2 has a close structural similarity to the SARS-CoV Mpro. A comparative study of amino acid sequences showed a 96 % identity between the Mpros of SARS-CoV-2 and SARS-CoV.…”

Section: Introductionmentioning

confidence: 97%

“…For one, ACE2 inhibitors have significant side effects, while RdRp inhibitors are not very specific. Also, it must be considered that enzymes such as RdRp require a prior Mpro‐dependent proteolytic release to reach their full function 17–20 …”

Section: Introductionmentioning

confidence: 99%

“…In fact, the Mpro of SARS‐CoV‐2 has a close structural similarity to the SARS‐CoV Mpro. A comparative study of amino acid sequences showed a 96 % identity between the Mpros of SARS‐CoV‐2 and SARS‐CoV 20 . However, the MERS‐CoV Mpro showed a lesser identity and similarity to SARS‐CoV‐2 Mpro 21 .…”

Section: Introductionmentioning

confidence: 99%

“…Also, it must be considered that enzymes such as RdRp require a prior Mpro-dependent proteolytic release to reach their full function. [17][18][19][20] From the structural standpoint, the SARS-CoV-2 Mpro is a hemodimer with two monomers. Each monomer of Mpro has 306 amino acid residues and contains three domains.…”

Section: Introductionmentioning

confidence: 99%

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Exploration of potential inhibitors for SARS‐CoV‐2 Mpro considering its mutants via structure‐based drug design, molecular docking, MD simulations, MM/PBSA, and DFT calculations

Ghasemlou

Uskoković

Sefidbakht

2022

Biotech and App Biochem

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The main protease (Mpro) of SARS-COV-2 plays a vital role in the viral life cycle and pathogenicity. Due to its specific attributes, this 3-chymotrypsin like protease can be a reliable target for the drug design to combat COVID-19. Since the advent of COVID-19, Mpro has undergone many mutations. Here, the impact of 10 mutations based on their frequency and five more based on their proximity to the active site was investigated. For comparison purposes, the docking process was also performed against the Mpros of SARS-COV and MERS-COV.Four inhibitors with the highest docking score (11b, α-ketoamide 13b, Nelfinavir, and PF-07321332) were selected for the structure-based ligand design via fragment replacement, and around 2000 new compounds were thus obtained. After the screening of these new compounds, the pharmacokinetic properties of the best ones were predicted. In the last step, comparative molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area calculations (MM/PBSA), and density functional theory calculations were performed. Among the 2000 newly designed compounds, three of them (NE1, NE2, and NE3), which were obtained by modifications of Nelfinavir, showed the highest affinity against all the Mpro targets. Together, NE1 compound is the best candidate for follow-up Mpro inhibition and drug development studies.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%