Identification of Key Interactions Between SARS-CoV-2 Main Protease and Inhibitor Drug Candidates

Yoshino, Ryunosuke; Yasuo, Nobuaki; Sekijima, Masakazu

doi:10.26434/chemrxiv.12009636

Cited by 4 publications

(5 citation statements)

References 27 publications

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“…Predicted binding sites in the viral main protease (M pro ) and receptor-binding domain (RBD) via CASTp, including the dimensions of the volumes and areas. Ser1, His41, Met49, Gly143, Phe140, Ser144, Cys145, His163, His164, Glu166, Pro168 and Gln189 have been determined in previous studies as lining the active sites of M pro [36,50], consistent with the prediction by CASTp as Pocket 1 (Table 1). A computational study to identify potential SARS-CoV-2 M pro inhibitors reported that the top compound docked into the M pro -binding cavity lined by residues His41, Met49, Tyr54, Phe140, Leu141, Asn142, Ser144, Cys145, His163, Met165, Glu166, Leu167, Pro168, Asp187, Arg188, Gln189 and Gln192 [28].…”

Section: Binding Site Analysis Of M Prosupporting

confidence: 85%

“…Considering the molecular interactions of the M pro , all the 36 compounds that met the ≤−7.5 kcal/mol threshold, except for ZINC000544552417 and ZINC000621286015, formed at least one hydrogen bonding with the M pro residues. Oxymetholone docked into pocket 1 (Figure 2d, and Tables 1 and 2), the known active site of the M pro [36,50]. It formed a hydrogen bond with Thr25 (bond length 2.81 Å); two with Glu166 (bond lengths 2.9 Å and 3.00 Å); and hydrophobic bonds with His41, Ser46, Thr45, Asn142, Gly143, Cys145, His164 and Met165.…”

Section: Characterization Of the M Pro -Ligand Interactionsmentioning

confidence: 99%

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Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin

et al. 2021

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The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome virus 2 (SARS-CoV-2) has impacted negatively on public health and socioeconomic status, globally. Although, there are currently no specific drugs approved, several existing drugs are being repurposed, but their successful outcomes are not guaranteed. Therefore, the search for novel therapeutics remains a priority. We screened for inhibitors of the SARS-CoV-2 main protease and the receptor-binding domain of the spike protein from an integrated library of African natural products, compounds generated from machine learning studies and antiviral drugs using AutoDock Vina. The binding mechanisms between the compounds and the proteins were characterized using LigPlot+ and molecular dynamics simulations techniques. The biological activities of the hit compounds were also predicted using a Bayesian-based approach. Six potential bioactive molecules NANPDB2245, NANPDB2403, fusidic acid, ZINC000095486008, ZINC0000556656943 and ZINC001645993538 were identified, all of which had plausible binding mechanisms with both viral receptors. Molecular dynamics simulations, including molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) computations revealed stable protein-ligand complexes with all the compounds having acceptable free binding energies <−15 kJ/mol with each receptor. NANPDB2245, NANPDB2403 and ZINC000095486008 were predicted as antivirals; ZINC000095486008 as a membrane permeability inhibitor; NANPDB2403 as a cell adhesion inhibitor and RNA-directed RNA polymerase inhibitor; and NANPDB2245 as a membrane integrity antagonist. Therefore, they have the potential to inhibit viral entry and replication. These drug-like molecules were predicted to possess attractive pharmacological profiles with negligible toxicity. Novel critical residues identified for both targets could aid in a better understanding of the binding mechanisms and design of fragment-based de novo inhibitors. The compounds are proposed as worthy of further in vitro assaying and as scaffolds for the development of novel SARS-CoV-2 therapeutic molecules.

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Section: Binding Site Analysis Of M Prosupporting

confidence: 85%

Section: Characterization Of the M Pro -Ligand Interactionsmentioning

confidence: 99%

Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin

et al. 2021

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“…The α-ketoamide-derived inhibitor interacts with 3CLpro, specifically with residues His41, His164, and Cys145 [20]. Three drug-like peptides were identified and shown to interact with His41, Gly143, and Glu166 of the 3CLpro [19]. The Glu166 is a potential pharmacophore for drug design and plays a key role in preventing 3CLpro dimerization [14].…”

Section: Pharmacophoric Hypothesis Based On Molecular Dynamics Simula...mentioning

confidence: 99%

“…Among the molecular targets, the Spike protein and the 3-chymotrypsin-like protease (3CLpro or Mpro, SARS-CoV-2 main protease) play key roles in vaccine and drug designs, respectively [14][15][16][17][18][19]. In particular, the 3CLpro cleaves 13 sites of two polyproteins, pp1a and pp1ab, which are results from translation of the genomic mRNA.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations Suggest Sars-Cov-2 3clpro Mutations in Beta and Omicron Variants do not Alter Binding Affinities for Cleavage Sites of Non-Structural Proteins

Amorim¹,

Souza²,

Guzzo³

et al. 2023

Preprint

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In the course of SARS-CoV-2 infection, the 3CL or nsp5 protease plays a pivotal role as the most important viral protease required for the maturation of viral proteins during host infection. Herein, we simulated for 500 ns 3CLproWT, 3CLproH41A, , 3CLproBeta, and 3CLproOmicron, in complex with the substrates nsp 4|5 and nsp 5|6. Our results show that mutations in the 3CLpro present in the SARS-CoV-2 variant of concerns (VOCs) did not lead to significant conformational changes or changes in substrate binding affinities. However, significantly high cleavage rates for the boundary between nsp4 and nsp5 were obtained for 3CLproBeta and 3CLproOmicron and may play a key role in the viral replication and virus fitness gain. Our molecular dynamics data suggest that the cleavage rate of nsp4|5 may be related to the increased amount of viral load observed for these VOCs, releasing more nsp4 than other non-structural proteins. Based on our hydrogen bonding analyses, we also discovered that Gly143 and Glu166 are key residues in substrate recognition, suggesting that these residues may be incorporated as pharmacophoric centers for Beta and Omicron variants in drug design. Our results suggest that Gly143 and Glu166 are essential residues to interact with Gln6 of the different substrates and, therefore, are potential broad-spectrum pharmacophoric centers of SARS-CoV-2 3CLpro.

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“…Потенциальная активность, сродство к клеточным мишеням, оценивается при помощи компьютерного моделирования (молекулярная динамика и стекинг) ввиду отсутствия доступных экспериментальных моделей заболевания. Среди этих отобранных препаратов -аналоги интерферона, лопинавир, ритонавир, симепревир, паритапревир, фавипиравир, ремдесивир, гидроксихлорохин, азитромицин и другие, причем многие из них используются для лечения СПИД и гепатита С, а также малярии [6][7][8][9]. Клиническая эффективность данных соединений при терапии COVID-19 в настоящее время находится в стадии изучения [10].…”

Section: возможные мишени для вируса Sars-cov-2 и противовирусные пре...unclassified

Promising compounds from natural sources against COVID-19

Андреев¹,

Shershakova²,

Kozhikhova³

et al. 2020

Russian Journal of Allergy

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The epidemic associated with the new Sars-CoV-2 coronavirus has affected almost all countries of the world and no reliable treatment for this infection exists yet. Many laboratories in the world are currently conducting intensive experimental and theoretical/in silico studies to find effective drugs specific for this disease (COVID-19), but unfortunately, it may take a long time before new drugs appear in the clinical practice. One of the currently widely accepted approaches for finding active compounds is based on the possibility of using existing drugs approved by government medical organizations (as the FDA). Their choice is based on screening, based on the use of computer models that evaluate the specific binding (energy minimization) of such drugs to target molecules that are important for the life cycle. Thus, a few well-known antiviral drugs against HIV, hepatitis C and others selected on this basis exerted an antiviral effect in vitro, but their real effectiveness was far from expected. It should be emphasized that the severe clinical manifestation of the disease is an acute respiratory distress syndrome, mediated by oxidative stress and an aggressive immune attack on its own cells. In this regard, the use of compounds with high antioxidant activity could have advantages both prophylactically and medically. There is a huge range of natural compounds, including official and traditional medicine, which represent valuable unlimited potential for COVID-19 therapy, the advantage of such compounds in their low toxicity. In this review, we tried to focus on the clinical and pharmacological properties of natural substances, mainly flavonoids, which can become promising drugs for the treatment and prevention of COVID-19. The review includes information on possible virus targets and antiviral drugs. Much attention is paid to the question of inhibition of viral activity. Based on published data, including structural features of various compounds, a prediction is made about the prospects of using these compounds as inhibitors of viral activity, as well as anti-inflammatory drugs for the treatment of COVID-19. An important step in the analysis of compounds was the study of the possibility of their interaction with cellular targets of the virus, as well as the ability to bind to the proteins of the Sars-CoV-2 virus itself.

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Identification of Key Interactions Between SARS-CoV-2 Main Protease and Inhibitor Drug Candidates

Cited by 4 publications

References 27 publications

Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin

Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin

Molecular Dynamics Simulations Suggest Sars-Cov-2 3clpro Mutations in Beta and Omicron Variants do not Alter Binding Affinities for Cleavage Sites of Non-Structural Proteins

Promising compounds from natural sources against COVID-19

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