Strong inhibition of M-Protease activity of Coronavirus by using PX-12 inhibitor based on ab initio ONIOM calculations

Monajemi, Hadieh; Zain, Sharifuddin M.

doi:10.1177/1747519820938025

Cited by 5 publications

(4 citation statements)

References 13 publications

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“…Ramos et al considered aldehyde derivatives. The covalent binding of inhibitor PX-12 and peptides to Mpro was simulated by the QM/MM method. − Regarding the S protein, the interactions of human ACE2 and hydroxychloroquine to S protein RBD were analyzed through QM/MM calculations. , …”

Section: Methods and Approachesmentioning

confidence: 99%

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Gao¹,

Wang²,

Chen³

et al. 2022

Chem. Rev.

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Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus–host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component in combating coronavirus disease 2019 (COVID-19) due to their low cost, their efficiency, and the fact that they are free from safety and ethical constraints. Additionally, the mechanism that governs the global evolution and transmission of SARS-CoV-2 cannot be revealed from individual experiments and was discovered by integrating genotyping of massive viral sequences, biophysical modeling of protein–protein interactions, deep mutational data, deep learning, and advanced mathematics. There exists a tsunami of literature on the molecular modeling, simulations, and predictions of SARS-CoV-2 and related developments of drugs, vaccines, antibodies, and diagnostics. To provide readers with a quick update about this literature, we present a comprehensive and systematic methodology-centered review. Aspects such as molecular biophysics, bioinformatics, cheminformatics, machine learning, and mathematics are discussed. This review will be beneficial to researchers who are looking for ways to contribute to SARS-CoV-2 studies and those who are interested in the status of the field.

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Section: Methods and Approachesmentioning

confidence: 99%

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Gao¹,

Wang²,

Chen³

et al. 2022

Chem. Rev.

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“…Nitrocefin [145] Mpro Interaction energy N3 [146] FBA-II inhibitors XO calculations Compound 1 [147] Aromatase Inhibitor Interaction energy Compound 6 [148] farnesyl pyrophosphate synthase Inhibitor…”

Section: Mechanism Of Covalent Inhibitionmentioning

confidence: 99%

QM/MM Studies on Enzyme Catalysis and Insight into Designing of New Inhibitors by ONIOM Approach: Recent Update

et al. 2023

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Computational enzymology is a rapidly developing area that uniquely provides deep insight into the fundamental processes of biological catalysis at the atomic level. Such in‐depth insight can ultimately be employed in designing potential inhibitors against the targets of interest. Computational enzymology covers a wide range of in‐silico approaches for investigating the enzyme‐catalyzed reaction mechanisms, among which combined quantum mechanics (QM) /molecular mechanics (MM) approaches have gained a lot of attention nowadays. This advanced approach generally involves a QM method (i. e. a method that estimates the electronic structure of the active site) and a simpler MM method (a method that includes the enzyme environment) to understand the enzymatic reactions. The QM/MM method has been widely tested in understanding the molecular mechanisms both at the structural and energetic levels and observed to best correlate with experimental studies of the enzymatic mechanism. It proposes a new mechanism that ultimately opens a new route for designing new potent, efficacious enzyme inhibitors. This review mainly covers wide applications of the ONIOM (Our own N‐layer Integrated molecular Orbital Molecular mechanics) method for decoding the enzymatic catalysis mechanism or designing potential small molecule inhibitors as treatment therapeutics in terms of free energy profiles. Moreover, this article also highlights employing QM/MM method in comprehending the mechanisms for drug metabolism and resistance (owing to mutations). This write‐up may encourage medicinal chemists and molecular biologists to explore this approach to propose more promising therapeutics to improve the quality of treatment.

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Section: Electrophilic Warheads In Covalent Sars-cov-2 M Pr...mentioning

confidence: 99%

“…Analysis of in silico and in vitro data demonstrated the strong antiviral activity of ebselen (IC 50 = 0.67 μM against SARS-CoV-2 M PRO ) and the capability to covalently bind the catalytic Cys 145 of SARS-CoV-2 M PRO . 15,106 To further explore the mechanism of covalent inhibition of this compound, a combination of docking and density functional theory (DFT) protocols clarified the ebselen ability to form a covalent adduct with Cys 145 by the formation of a selenyl sulfide bond. 107 In Figure 45b the mechanism of action of ebselen is shown: the first step is the activation of the thiol group of Cys 145 through deprotonation mediated by His 41 ; subsequently, the activated thiolate performs the nucleophilic attack on the electrophilic selenium atom, determining the opening of the 5membered ring and the formation of selenyl sulfide bond, responsible for the covalent inhibition of the target.…”

Section: Carbonyl Warheadmentioning

confidence: 99%

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

et al. 2022

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The viral main protease is one of the most attractive targets among all key enzymes involved in the SARS-CoV-2 life cycle. Covalent inhibition of the cysteine 145 of SARS-CoV-2 M PRO with selective antiviral drugs will arrest the replication process of the virus without affecting human catalytic pathways. In this Perspective, we analyzed the in silico, in vitro, and in vivo data of the most representative examples of covalent SARS-CoV-2 M PRO inhibitors reported in the literature to date. In particular, the studied molecules were classified into eight different categories according to their reactive electrophilic warheads, highlighting the differences between their reversible/irreversible mechanism of inhibition. Furthermore, the analyses of the most recurrent pharmacophoric moieties and stereochemistry of chiral carbons were reported. The analyses of noncovalent and covalent in silico protocols, provided in this Perspective, would be useful for the scientific community to discover new and more efficient covalent SARS-CoV-2 M PRO inhibitors.

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Strong inhibition of M-Protease activity of Coronavirus by using PX-12 inhibitor based on ab initio ONIOM calculations

Cited by 5 publications

References 13 publications

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

QM/MM Studies on Enzyme Catalysis and Insight into Designing of New Inhibitors by ONIOM Approach: Recent Update

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

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