#SARS-CoV-2 Mpro inhibitors

[pharmafocusasiamagazine]

The SARS-CoV-2 pandemic has required the development of new methods for rapidly developing effective vaccines and drugs to treat COVID- 19 patients. There are approximately 12,000 existing drugs, approved natural products, and clinical trials candidates whose safety in man has already been established. Computational repurposing of these drugs, where mathematical methods are used to simulate their interactions with key proteins in the virus, is a rapid way to find new treatments for SARS-CoV-2.

For more info visit: https://www.pharmafocusasia.com/research-development/computational-repurposing-drugs

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Next-gen Mpro inhibitor: Promising new drug candidate against Omicron and other SARS-CoV-2 variants - News-Medical.Net

http://dlvr.it/SlKwbx

[juniperpublishersna]

In Silico Molecular Docking Study on Selective Cyclooxygenase-2 Inhibitor Drugs For SARS-Cov-2 Active Main Protease

Abstract

The coronavirus (COVID-19) pandemic became one of the most important disease problem across the globe for last few years since there is no recommended efficacious drugs in the market. So, there is an urgent need for efficient drugs to treat this disease in the near future. In the present study, molecular docking analyses of selective cyclooxygenase-2 inhibitor drugs (Celecoxib, Rofecoxib, Valdecoxib, Lumiracoxib, Parecoxib, Etoricoxib, and Firocoxib) were performed against the therapeutic target proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) enzyme into the catalytic active site. On the other hand, these drugs were compared with standard drugs such as Favipiravir, Chloroquine and Hydroxychloroquine to understand the binding sites and find the best poses. The results revealed that all the selective cyclooxygenase-2 inhibitor drugs (except Lumiracoxib) showed a better binding affinity against SARS-CoV-2 Mpro enzyme than the standard drugs. Among them, Etoricoxib (-9.40 kcal/mol) have shown the best binding affinity. As a result, this study shows that these selective cyclooxygenase-2 inhibitor drugs might be interesting lead compounds to discover more potent SARS-CoV-2 Mpro inhibitors and find to cure severe COVID-19 disease with better drugs.

Keywords: Molecular docking; Coronavirus; COVID-19; Cyclooxygenase-2 inhibitor; In silico

Introduction

An outbreak was reported by the World Health Organization (WHO) in Wuhan, China in December 2019. This epidemic was named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) on January 30, 2020 [1,2]. In the second week of March 2020, the epidemic was declared global pandemic and within a few months the number of cases increased to 4 million and the death rate increased significantly [3]. The viral agent causing the outbreak belongs to the betacoronavirus family [1,2]. The disease caused by the SARS-CoV-2 factor is highly contagious [4]. This illness is basically a type of viral infection that spreads rapidly through respiratory droplet and direct contact. This infection has many symptoms, such as fever, cough, shortness of breath and gastrointestinal diseases [3,5-7]. The COVID-19 epidemic, in addition to threatening human health, has also had negative effects in areas such as the global economy around the world [3].

Cyclooxygenases are enzymes that allow free fatty acids to convert into cyclic endoperoxides. Arachidonic acid and some other fatty acids are exposed to the action of this enzyme and forming various prostaglandins [8,9]. Studies have shown that there are two different isoforms of the enzyme [8]. The first isoform, known as COX-1, is the structural form and is continuously present in the region in which it is produced. The COX-2 isoform is the inducible form [10,11]. This enzyme isoform is induced, especially in cases that cause inflammation. As a result of increased expression of the enzyme COX-2, abundant prostanoids are formed. In the presence of systemic infection, this rate increases even more. It has been found that this isoform increases in various pathologies, such as certain types of cancer and diseases of the central nervous system [8].

Microorganisms stimulate processes associated with the immune system and inflammatory events in the tissues they attack. Elimination the inflammatory condition that occurs is very important for the treatment of diseases caused by infection. In this context, polyunsaturated fatty acids (PUFA) and their metabolites play a very important role. In studies, lipid derivatives have been found to kill various microorganisms [12]. In general, PUFA kill microbes by their direct effect on microbial cell membranes. Arachidonic, eicosapentaenoic and docosahexaenoic acids act as endogenous antibacterial and antifungals. These lipid molecules also have antiviral, antiparazit and immunomodulatory effects. Cytokines involved in cell defense induce the release of PUFA from the cell membrane. These lipid molecules provide the formation of lipoxins and resolvins that have antimicrobial effects [13]. A study has shown that COX inhibition protects the virus from spreading from cell to cell by a mechanism that inhibits cytomegalovirus maturation [14]. COX-2 inhibitors such as etoricoxib or celecoxib are drugs that contribute to a decrease in mortality in severe influenza. COX-2 inhibitors are thought to be secure in the treatment of COVID-19 and may reduce disease progression in groups of high risky elderly patients with pneumonia due to their treatment of inflammation [15].

It has also been shown in previous studies that the severity and course of the inflammatory process differ decidedly between male and female [16]. Simona Pace et al. found that isolated lipopolysaccharide causes more PGE2 production in males and this may be due to increased COX-2 expression [17]. It is also thought that PGE2 levels, which are an important lipid agent and enhance more in men, may be a factor that explains the more severe disease formation condition of COVID-19 in men [16]. The parallelism of the increase in PGE2 and disease rates suggests that COX-2 inhibitors may be effective in treatment.

The aim of this study is to evaluate the place of COX-2 enzyme inhibition in COVID-19 treatment as in silico. In addition to the effect of these drugs (Scheme 1) on suppressing inflammation and reducing the severity of the disease, the ability to bind to the SARSCoV- 2 factor will be evaluated. This attachment is very important in terms of preventing the viral factor from entering the cell and preventing the effects of the disease on the body.

Material and Methods

The AutoDock 4.2 molecular docking program was used to find best binding interactions of selected selective cyclooxygenase-2 inhibitor drugs against SARS-CoV-2. The three-dimensional (3D) crystal structure of the protein Mpro was retrieved from Protein Data Bank (PDB) (PDB ID: 6LU7) [18]. The 3D structure of the drugs was downloaded from the PubChem (https://pubchem. ncbi.nlm.nih.gov/) in structure-data file format. The most suitable of the possible binding modes obtained as a result of the Molecular Docking processes were determined with Autodock 4.2, and their analyzes and visuals were obtained with the Biovia Discovery Studio Visualizer 2020 program [19-21]. In the present study, a selective cyclooxygenase-2 (COX-2) inhibitor drugs Celecoxib, Rofecoxib, Valdecoxib, Lumiracoxib, Parecoxib, Etoricoxib, and Firocoxib molecules were used for docking procedures. Also, Favipiravir, Chloroquine and Hydroxychloroquine were used as standard drugs for comparison.

Results and Discussion

The docking analysis result of the molecules and standards Celecoxib, Rofecoxib, Valdecoxib, Lumiracoxib, Parecoxib, Etoricoxib, Firocoxib, Favipiravir, Chloroquine and Hydroxychloroquine as inhibitors of SARS-CoV-2 (PDB: 6LU7) including binding energy, inhibition constant and important interactions at the active site are demonstrated in Table 1.

The protein-ligand interaction study revealed that the selective cyclooxygenase-2 inhibitor drugs are binding at the active site of SARS-CoV-2 Mpro protein with the best poses ranging from -6.27 to -9.40 kcal/mol (Table 1). In the current work, all the selective cyclooxygenase-2 inhibitor drugs showed better binding affinity then the standard drugs Favipiravir, Chloroquine, and Hydroxychloroquine (binding affinities of -4.21, -7.22, and -6.26 kcal/mol, respectively), except the Lumiracoxib. Among the best docking scores, only one drug (Lumiracoxib) has been shown the bind in a different region, then the rest of drugs (including standard drugs) and the binding energy of this drug was lowest (-6.27 kcal/ mol) among other drugs that were docked in this study (Figure 1). The best binding affinity (-9.40 kcal/mol) was observed with the drug of Etoricoxib, which have several important amino acid interactions, including hydrogen bonds with Thr 190 and Gln 192, and pi-alkyl interaction with Met 49, Pro 52, Cys, 145, Met 165, and Arg 188. The great binding affinities were also obtained with the drugs of Celecoxib, Rofecoxib, Valdecoxib, and Parecoxib, which had close binding energies to each other’s (-8.24, -8.51, -8.83, and -8.89 kcal/mol, respectively). The most important interactions with these compounds were with Cys 145 (hydrogen bonding), His 41 (pi-carbon bonding), Met 49 and Met 165 (Pialkyl interactions) (Figure 2). The moderate binding affinity was observed with the drug of Firocoxib (-7.88 kcal/mol). This drug also has some hydrogen bounds (His 41, Cys 145, Thr 190 and Gln 192), Pi-alkyl interactions (Met 49, Cys 145, His 163, and Met 165) and Pi-sigma interaction with Gln 189 (Figure 2).

In general, all the docked selective cyclooxygenase-2 inhibitor drugs showed great binding affinities against SARS-CoV-2 Mpro enzyme by having important interactions on the active site. As shown in Figure 1, only one drug (Lumiracoxib) found to bind different binding site which is not favorable for high binding affinities. Some key amino acids are important on the active site for great binding affinities such as Gly 143, Cys 145, Thr 190, and Gln 192 for hydrogen bonding, His 41 (for Pi-carbon interactions), and Met 49 and Met 165 (for Pi-alkyl interactions).

Conclusion

In summary, we have performed molecular docking of the selective cyclooxygenase-2 inhibitor drugs (Celecoxib, Rofecoxib, Valdecoxib, Lumiracoxib, Parecoxib, Etoricoxib, and Firocoxib) with the important therapeutic target protein of SARS-CoV-2 and compared them with the standard drugs Favipiravir, Chloroquine and Hydroxychloroquine. The obtained dock scores demonstrated that all the selective cyclooxygenase-2 inhibitor drugs (except Lumiracoxib) showed a better binding affinity against SARSCoV- 2 Mpro enzyme than the standard drugs. More specifically, Etoricoxib (-9.40 kcal/mol) have shown the best binding affinity. This docking study indicates that these selective cyclooxygenase-2 inhibitor drugs might be useful lead molecules to discover potent and less toxic SARS-CoV-2 drugs in the near future.

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COVID-19 Treatments: Antiviral and Anti-inflammation

COVID-19

Treatments: Antiviral and Anti-inflammation

Antiviral

•Remdesivir and Nucleoside Analogues

•Chloroquine and its Family Members

Anti-inflammation

Antiviral Natural Products

COVID-19 Related Compound Libraries

The pandemic outbreak of coronavirus disease 2019 (COVID-19) has spread all over the world and has been a great threat to humans for absence of specific effective anti-viral treatments. It is urgent to identify effective, safe, and available treatment strategy for COVID-19.

As COVID-19 is a viral infectious disease with major symptoms of fever and pneumonia, antiviral and anti-inflammation related supportive therapies are important treatments for severe cases.

Schematic of SARS-CoV-2 infection[1-3]

COVID-19 in caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2). SARS-CoV-2 belongs to coronavirus (CoV) who have four main structural proteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins.

After primed by a protease called TMPRSS2 (transmembrane protease, serine 2), the S protein mediates the CoV entry into host cells by attaching to a cellular receptor named ACE2, followed by fusion between virus and host cell membranes. Genome replication and subgenomic RNA transcription after entry carry on with the participation of many nonstructural proteins such as Mpro (main protease or 3CLpro), PLpro (papain-like protease) and RdRp (RNA-dependent RNA polymerase). Then the structural proteins are translated, assembled into mature virions, and released via vesicles by exocytosis.

What’s worth mentioning, the vast release of cytokines (such as IL-1β, GM-CSF, IL-6, IL-10) by the immune system in response to severe infection of SARS-CoV-2 called cytokine storm contributes largely to the mortality of COVID-19.

Antiviral

All the proteins and subcellular structures participated in the life cycle of CoVs are promising targets for treatment of disease caused by CoVs. It is inspiring that numbers of promising agents with potential of antiviral have been reported to deal with COVID-19.

GroupCompoundMechanism of action

Inhibitors of viral protein synthesis

Lopinavir

[4]

Ritonavir

[4]

Protease inhibitor.

Inhibitors of viral RNA

polymerase/RNA synthesis

Remdesivir

[5]

GS-443902

[6]

GS-443902 trisodium

[6]

Favipiravir

[7]

Ribavirin

[8]

Nucleoside analogue, prodrug, RdRp inhibitor.

Inhibitors of viral entry

Chloroquine

[5]

Chloroquine phosphate

[5]

Hydroxychloroquine sulfate

[5]

Increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of ACE2.

Camostat mesylate

[9]

Nafamostat mesylate

[10]

Inhibiting Sprotein priming and S protein-driven cell entry of SARS-CoV-2 mediating by TMPRSS2.

Umifenovir hydrochloride

[11]

Might inhibit the fusion process.

Inhibitors of Mpro

Ebselen

[12]

Carmofur

[12]

PX-12

[12]

SARS-CoV-2-IN-1

[13]

Binding with Mpro of SARS-CoV-2.

Inhibitor of viral proteins trafficking

Ivermectin

[14]

Inhibit importin α/β-mediated nuclear transport, which in turn blocks the nuclear trafficking of viral proteins.

Enhance antiviral immune response

Nitazoxanide

[15]

Interferon-beta 1

[16]

Regulates inflammation pathways.

Remdesivir and Nucleoside Analogues

Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and function as inhibitor of RdRp. Remdesivir has been reported to inhibit numbers of RNA viruses (including SARS-CoV, MERS-CoV and SARS-CoV-2) infection in cultured cells and showed effects for treating COVID-19 in clinical. Except for remdesivir, its metabolites and several nucleoside analogues are also reported to have the antiviral ability.

ConditionCompoundMechanismStatus

Anticancer

Nucleoside & Nucleotide

Analogues

Gemcitabine

Targets DNA polymeraseApproved

5-Azacytidine

Traps DNA methyltransferaseApproved

Cytarabine

Targets DNA polymeraseApproved

Antiviral

Nucleoside & Nucleotide

Analogues

Remdesivir

[5]

GS-443902

[6]

GS-443902 trisodium

[5]

Remdesivir nucleoside monophosphate

Remdesivir and its metabolites, inhibitors of RdRp.Phase III

Favipiravir

Targets RNA-dependent RNA polymerase (RdRp)Approved

Tenofovir

Targets nucleotide reverse transcriptaseApproved

Asunaprevir

Targets NS3 proteaseApproved

Antibacterial

Nucleoside & Nucleotide

Analogues

Linezolid

Inhibits bacterial protein synthesisApproved

Nitrofurantoin

Inhibits bacterial DNA, RNA and protein synthesisApproved

Isoniazid

Acts on the mycobacterial cell wallApproved

Chloroquine and Its Family Members

Chloroquine is a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broad spectrum antiviral drug. Chloroquine is known to block virus infection by inhibiting the fusion of virus and host cell by increasing endosomal pH and interfering the function of ACE2. Chloroquine and hydroxychloroquine are proposed to be used to treat COVID-19 in clinical trials.

Subfamily Members

Relationship

Mechanism of Action

Clinical Status and Indication

Chloroquine Subfamily

Chloroquine

Representative DrugAutophagy, RNA-dependent

RNA polymerase, TLR

Approved:

Malaria, Tumor, Rheumatoid Arthritis,

COVID-19, etc

Preclinical Research:

Chikungunya Virus

Didesethyl Chloroquine

Major Metabolite of

ChloroquineAutophagy, RNA-dependent

RNA polymerase

Preclinical Research:

Malaria, Chikungunya Virus

Hydroxychloroquine

Less Toxic Metabolite of

ChloroquineAutophagy, RNA-dependent

RNA polymerase, TLR

Approved:

Malaria, Tumor, Rheumatoid Arthritis,

COVID-19, etc

Preclinical Research:

Chikungunya Virus

Cletoquine

Major Active Metabolite of

HydroxychloroquineAutophagy, RNA-dependent

RNA polymerase

Preclinical Research:

Chikungunya Virus,

Antirheumatic

Ferroquine Subfamily

Ferroquine

Chloroquine AnalogAutophagy, Ferroptosis

Phase II:

Malaria

Preclinical Research:

Tumor, Virus

Desmethyl Ferroquine

Major Metabolite of

FerroquineAutophagy, RNA-dependent

RNA polymerase

Preclinical Research:

Malaria, Virus

SARS-CoV-IN 1

SARS-CoV-IN 2

SARS-CoV-IN 3

Derivative of Ferroquine

Preclinical Research:

Malaria, SARS-CoV

Other Subfamily

Primaquine

Chloroquine AnalogROS

Approved:

Malaria, HIV

Mefloquine

Chloroquine AnalogHeme polymerase

Approved:

Malaria

Preclinical Research:

Osteoporosis

Amodiaquine

Chloroquine AnalogHeme polymerase

Approved:

Malaria

Preclinical Research:

Ebola Virus

N-Desethyl amodiaquine

Major Active Metabolite of

Amodiaquine

Preclinical Research:

Malaria

Anti-inflammation

Current management for COVID-19 is supportive therapy as there is still no effective cure.

Respiratory failure from acute respiratory distress syndrome (ARDS) is reported to be the leading cause of mortality of COVID-19. The primary cause of ARDS is cytokine storm characterized by excessive and uncontrolled release of pro-inflammatory cytokines (such as IL-6, IL-1, IL-17, IL-2, GM-CSF) after infection. So anti-inflammation are the most important supportive therapy for patients with severe COVID-19.

Therapeutic options for anti-inflammation in patients with COVID-19 include steroids, selective cytokine blockade, JAK inhibition, and intravenous immunoglobulin.

CompoundMechanism of action

Methylprednisolone

[17]

Glucocorticoids suppress cytokine storm manifestations in patients with COVID-19.

Dexamethasone

[18]

A glucocorticoid receptor agonist and the first drug save lives by one-third among patients critically ill with COVID-19.

Anakinra

[19]

An interleukin-1 receptor (IL-1R) antagonist may be beneficial for treating severe COVID-19 patients.

Tocilizumab

[20]

Sarilumab

[21]

Recombinant human IL-6 monoclonal antibody thus blocking IL-6 signaling and its mediated inflammatory response, as a therapeutic option against COVID-19.

Baricitinib

[22]

A dual inhibitor of JAK and AAK1 (AP2-associated protein kinase 1, a regulator ofendocytosis) as the possible candidate for treatment of COVID-19 because of its relative safety and high affinity.

Chloroquine

Hydroxychloroquine

[5]

CQ and HCQ can regulate immune system by affecting cell signaling and production of pro-inflammatory cytokines.

Melatonin

[23]

Plays a role of adjuvant medication in the regulation of immune system, inflammation and oxidation stress.

Antiviral Natural Products

Many natural products have broad-spectrum antiviral effects by inhibiting various steps in viral infection and replication. Natural products can also function as immunomodulators, suppressing inflammatory reaction. Some of them are reported to have the potential of inhibiting coronavirus and may be promising candidate agents for COVID-19. Take emodin as an example, it has been shown to inhibit the interaction of SARS-CoV S protein with its receptor ACE2[24].

Forsythia suspensa

Lonicera japonica Thunb

Ephedra

Semen Armeniacae amarum

Isatis indigotica L

Dryopteris crassirhizoma Nakai

Houttuynia cordata

Pogostemon cablin

Rheum

Rhodiola rosea

Glycyrrhiza uralensis

Menthol

COVID-19 Related Compound Libraries

It is urgent to develop drugs to treat COVID-19 quickly. The drug repurposing using visual screening technology in clinical and approved compounds can greatly shorten timeline and improve the efficiency of the development of anti-COVID-19 drugs.

As mentioned above, the reported candidate drugs for COVID-19 include agents targeting viruses (such as HIV and SARS-CoV) and inflammation. It indicates that all the antiviral, anti-infection and anti-inflammation related chemicals may have the potential to be effective in treatment of COVID-19.

Compound libraryDescription

Anti-COVID-19 Compound Library

Chemicals with potential anti-COVID-19 activity targeted 3CL protease, Spike protein, NSP15, RdRp, PLpro and

ACE2 collected by visual screening in

Drug Repurposing Compound Library (HY-L035)

.

Anti-Virus Compound Library

Compound library containing all kinds of molecules with anti-virus activity.

Anti-Infection Compound Library

Antiviral, antibacterial, antifungal and antiparasitic compound library.

Immunology/Inflammation Compound Library

Antiviral, antibacterial, antifungal and antiparasitic compound library.

Anti-infection:

Antibiotic

Arenavirus

Bacterial

CMV

EBV

Enterovirus

Filovirus

Fungal

HBV

HCV

HCV Protease

HIV

HIV Protease

HPV

HSV

Influenza Virus

Orthopoxvirus

Parasite

Reverse Transcriptase

RSV

SARS-CoV

TMV

Virus Protease

VSV

References:

[1].   Azkur, A.K., et al., Immune response to SARS‐CoV‐2 and mechanisms of immunopathological changes in COVID‐19. Allergy, 2020.

[2].   Strope, J.D., C.H.C. PharmD and W.D. Figg, TMPRSS2: Potential Biomarker for COVID‐19 Outcomes. The Journal of Clinical Pharmacology, 2020. 60(7): p. 801-807.

[3].   Tay, M.Z., et al., The trinity of COVID-19: immunity, inflammation and intervention. Nature reviews. Immunology, 2020. 20(6): p. 363-374.

[4].   Lim, J., et al., Case of the Index Patient Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Pneumonia Monitored by Quantitative RT-PCR. Journal of Korean Medical Science, 2020. 35(6).

[5].   Wang, M., et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 2020. 30(3): p. 269-271.

[6].   Yang, K., What do we know about remdesivir drug interactions? Clinical and Translational Science, 2020.

[7].   Cai, Q., et al., Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering, 2020.

[8].   Elfiky, A.A., Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sciences, 2020. 248: p. 117477-117477.

[9].   Hoffmann, M., et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 2020. 181(2): p. 271-280.e8.

[10].   Hoffmann, M., et al., Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19. Antimicrobial Agents and Chemotherapy, 2020. 64(6).

[11].   Deng, L., et al., Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. Journal of Infection, 2020. 81(1): p. e1-e5.

[12].   Jin, Z., et al., Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 2020.

[13].   Zhang, L., et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science (American Association for the Advancement of Science), 2020. 368(6489): p. 409.

[14].   Sharun, K., et al., Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19. Annals of Clinical Microbiology and Antimicrobials, 2020. 19(1).

[15].   Toby Pepperrell, V.P.A.O., Review of safety and minimum pricing of nitazoxanide for potential treatment of COVID-19. Journal of Virus Eradication, 2020. 6: p. 52-60.

[16].   Hung, I.F., et al., Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet (British edition), 2020. 395(10238): p. 1695-1704.

[17].   Wang, Y., et al., A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduction and Targeted Therapy, 2020. 5(1).

[18].   Ledford, H., Coronavirus Breakthrough: Dexamethasone Is First Drug Shown to Save Lives. NATURE, 2020.

[19].   Dimopoulos, G., et al., FAVORABLE ANAKINRA RESPONSES IN SEVERE COVID-19 PATIENTS WITH SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS. Cell host & microbe, 2020.

[20].   Luo, P., et al., Tocilizumab treatment in COVID‐19: A single center experience. Journal of Medical Virology, 2020. 92(7): p. 814-818.

[21].   Benucci, M., et al., COVID‐19 pneumonia treated with Sarilumab: A clinical series of eight patients. Journal of Medical Virology, 2020.

[22].   Cantini, F., et al., Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. The Journal of infection, 2020.

[23].   Rui Zhang, X.W.L.N., COVID-19: Melatonin as a potential adjuvant treatment. Life Sciences, 2020. 250(117583).

[24].   Ho, T., et al., Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Research, 2007. 74(2): p. 92-101.

[mi6-rogue]

Novel inhibitors against COVID-19 main protease suppressed viral infection

Preliminary report; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can cause severe disease with high mortality rates, especially among older and vulnerable populations. Despite the recent success of vaccines and approval of first-generation anti-viral inhibitor against SARS-CoV-2, an expanded arsenal of anti-viral compounds that limit viral replication and ameliorate disease severity is still urgently needed in light of the continued emergence of viral variants of concern (VOC). The main protease (Mpro) of SARS-CoV-2 is the major non-structural protein required for the processing of viral polypeptides encoded by the open reading frame 1 (ORF1) and ultimately replication. Structural conservation of Mpro among SARS-CoV-2 variants make this protein an attractive target for the anti-viral inhibition by small molecules. Here, we developed a structure-based in-silico screening of approximately 11 million compounds in ZINC15 database inhibiting Mpro, which prioritized 9 lead compounds for the subsequent in vitro validation in SARS-CoV-2 replication assays using both Vero and Calu-3 cells. We validated three of these compounds significantly inhibited SARS-CoV-2 replication in the micromolar range. In summary, our study identified novel small-molecules significantly suppressed infection and replication of SARS-CoV-2 in human cells. https://www.biorxiv.org/content/10.1101/2022.11.05.515305v1?rss=1%22&utm_source=dlvr.it&utm_medium=tumblr Read more ↓

[health28]

Scientists identify papain-like protease inhibitor against COVID-19

Scientists identify papain-like protease inhibitor against COVID-19

In a recent study posted to the bioRxiv* preprint server, researchers identified a papain-like protease inhibitor for treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Study: Identification of a Papain-Like Protease Inhibitor with Potential for Repurposing in Combination with an Mpro Protease Inhibitor for Treatment of SARS-CoV-2. Image Credit: MIA…

[market-insider]

Drug Discovery Informatics Market Size Worth $5.63 Billion By 2028

The global drug discovery informatics market size is expected to reach USD 5.63 billion by 2028 registering a CAGR of 11.3% over the forecast period, according to a new report by Grand View Research, Inc. Use of drug discovery software for gaining market intelligence owing to several advantages, such as rapid drug design & synthesis, efficient tracking of disease evolution, and data integrity management, has increased significantly among the researchers in the recent years, driving the industry growth.

The growing demand for novel molecules is driving the adoption of informatics solutions targeted towards speeding up the entire drug discovery process by identifying rational drug molecules via the target macromolecule interaction. Companies operating in the market are receiving funding for expanding their drug discovery platforms, further supplementing the market growth. For instance, in September 2020, Ardigen signed an agreement with the National Centre for Research and Development to access its funding for developing novel technology.

This technology was aimed at revolutionizing the development of T-cell receptors-based therapies for immuno-oncology. Ardigen has previously developed a neoantigen prediction platform namely, ArdImmune Vax, which deploys ready-to-use Artificial Intelligence (AI) and bioinformatics solutions for the identification of optimal sets of neoantigens as targets for adoptive cell therapies and cancer vaccines. In addition, chemical informatics solutions have gained considerable traction in the past year, particularly in addressing the needs associated with the recent Covid-19 pandemic.

For instance, a research study performed in January 2021 showcased the application of chemical digital solutions in accelerating the search of SARS-CoV-2 Mpro inhibitors by data analysis of previous activity data of SARS-CoV main protease (Mpro) inhibitors. In addition, the QSAR models helped in the data mining of molecules for rapid Covid-19 drug discovery. Hence, the need to facilitate drug development for Covid-19 is expected to propel the industry expansion over the coming years.

Gain deeper insights on the market and receive your free copy with TOC now @: https://www.grandviewresearch.com/industry-analysis/drug-discovery-informatics-market/request/rs15

[mhealthyliving]

Pfizer shares in vitro efficacy of novel COVID-19 oral treatment against omicron variant

Pfizer shares in vitro efficacy of novel COVID-19 oral treatment against omicron variant

Pfizer Inc. (NYSE: PFE) today shared results from multiple studies demonstrating that the in vitro efficacy of nirmatrelvir, the active main protease (Mpro) inhibitor of PAXLOVID™ (nirmatrelvir [PF-07321332] tablets and ritonavir tablets), is maintained against the SARS-CoV-2 variant Omicron. Taken together, these in vitro studies suggest that PAXLOVID has the potential to maintain plasma…

[whitecoatsapp]

Lactoferrin-derived Peptides can be Potential Inhibitors of SARS-CoV-2

A global effort is in the process to identify drugs for the treatment of COVID-19. Mpro (main protease) plays an important role in the virus life cycle, and the lack of this protease in humans makes it an intuitive choice for antiviral drug targets. Lactoferrin (LF), a glycoprotein exhibits antiviral properties in vitro against SARS- CoV that is closely related to SARS-CoV-2.

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New insights into structural stability of SARS-CoV-2 main protease

In a latest bioRxiv* preprint paper, researchers from the US and Italy utilized molecular dynamics simulations and revealed that the conformational stability of the SARS-CoV-2 binding web site, sure inhibitors, and the hydrogen bond networks of the viral fundamental protease (Mprofessional) are extremely delicate to protonation assignments.

The principle protease (Mprofessional) of extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of the continuing coronavirus illness (COVID-19) pandemic, performs a key position within the viral life cycle by facilitating and catalyzing the cleavage of SARS-CoV-2 covalently conjoined proteins.

Extra particularly, Mprofessional enzyme is a structurally conserved homodimer amongst coronaviruses, which makes it a reasonably enticing goal for the event of antiviral therapeutics. Just lately, a plethora of excessive decision apo and inhibitor-bound constructions of Mprofessional have been decided, enabling, in flip a structure-based drug design.

From the chemical perspective, Mprofessional is a cysteine protease characterised by a non-canonical histidine-cysteine (Cys-His) catalytic dyad. Along with His41-Cys145, Mprofessional harbors quite a lot of histidines – together with His163, His164, and His172.

The protonation states of the aforementioned histidines and the catalytic nucleophile Cys145 have been mentioned in earlier analysis research on SARS-CoV-1 Mprofessional (which causes authentic SARS), however not for SARS-CoV-2. Nevertheless, given the urgent want for efficacious remedy choices in our battle towards COVID-19, the hunt for Mprofessional inhibitors has been intensified.

For instance, a number of notable inhibitors have been recognized, and their crystal constructions launched, similar to alpha-ketoamides and peptidomimetic N3. These inhibitor-bound constructions are certainly distinctive beginning factors for additional drug optimization methods.

On this new research, a analysis group led by James C. Gumbart of the Georgia Institute of Expertise in Atlanta, aimed to find out the structural stability of SARS-CoV-2 Mprofessional as a perform of the protonation assignments for histidine and cysteine residues. The analysis was a collaborative effort between Georgia Institute of Expertise, the College of L’Aquila, CNR Institute of Nanoscience, the College of Tennessee, Knoxville, the Université de Lorraine,  the College of Illinois at Urbana-Champaign, Oak Ridge Nationwide Laboratory and Novartis Institutes for BioMedical Analysis.

Mpro dimer construction and binding web site interactions (PDB entry 6WQF). Mpro homodimer with the three domains illustrated and coloration coded as follows: Area I (darkish orange), area II (gold), and area III (gentle inexperienced/darkish inexperienced monomer A/B) with the catalytic dyad residues, His41 and Cys145 (rendered in licorice).

Methodological strategy

“We investigated the consequences on the structural properties of the apo and ligand-bound techniques by altering the protonation state of the catalytic dyad, Cys145 and His41, in addition to these of three histidines close to the substrate binding web site, His163, His164, and His172”, research authors summarize their methodological strategy.

Making an allowance for kindred ambiguity within the protonation states of SARS-CoV-2 Mprofessional, the researchers have appeared into the soundness of 12 potential protonation states of the protease. Detailed molecular dynamics simulations of apo and inhibitor-bound Mprofessional dimers have been carried out for every state, with subsequent evaluation of the ensuing structural and dynamical properties.

Hydrogen bonding was assessed for related residues of the protein, in addition to between the sure inhibitors and the protein. Lastly, two inhibitors have been studied intimately: peptidomimetic N3 and a really potent alpha-ketoamide.

A number of protonation combos

This research discovered that the protonated His41/deprotonated Cys145 state of the catalytic dyad is definitely unstable within the crystal construction conformations, as evidenced by elevated root-mean-square deviation, modified hydrogen bonding patterns, and disentangling of the inhibitors. Nonetheless, this state might exist as a transient response intermediate.

The researchers have additionally proven that His163 and His172 protonation states lead to substantial perturbations to a number of hydrogen bonds compared to crystal construction conformations.

Moreover, decreased pocket quantity was usually noticed within the simulations for the HP163 state. On the identical time, free-energy calculations confirmed decreased affinity for each examined inhibitors on this state, which qualitatively traces the noticed hydrogen bonding reductions.

In distinction to the opposite histidines, this analysis group has decided that a number of protonation combos are viable for the His41-His164 pair. Due to this fact, these residues might tackle completely different protonation states throughout the protein cleavage course of.

Hydrogen bonding within the S1 pocket. Instance configurations of A) HD41-HE164 attribute of strong S1 pocket interactions, B) HE41-HD164-HP172 illustrating the rupture of the S1’-Glu166 interplay and lack of the His163-Tyr161 hydrogen bond, and C) HE41-HP163-HD164 depicting the lack of the Tyr161 hydrogen bond donation and the His172-Glu166 interplay.

Implications for drug enchancment and design

“Our outcomes illustrate the significance of utilizing acceptable histidine protonation states to precisely mannequin the construction and dynamics of SARS-CoV-2 Mprofessional in each the apo and inhibitor-bound states, a crucial prerequisite for drug-design efforts”, summarize research authors on this bioRxiv paper.

In different phrases, an important protonation states of Mprofessional histidines must be thought-about for optimization efforts of N3 peptidomimetic and alpha-ketoamide, in addition to for the rational and focused design of different inhibitors.

Nonetheless, in silico high-throughput screens of latest potential inhibitors will profit from being carried out on every of the protonation states thought-about on this paper, primarily to make it possible when ligand is current. It will undoubtedly be a recurring theme in additional analysis endeavors on this matter.

Ketoamide hydrogen bonding within the HE41-HD164 protonation state. In each panels, hydrogen bonds between the ligand (gentle inexperienced licorice) and the protein are indicated with a blue line, whereas these with water or between protein residues are pink. A) Area across the crystallographic water. B) conformation wherein the His164 has rotated, making a hydrogen bond with the spine of Met162. The crystallographic water has been launched.

*Necessary Discover

bioRxiv publishes preliminary scientific experiences that aren’t peer-reviewed and, subsequently, shouldn’t be thought to be conclusive, information scientific observe/health-related habits, or handled as established data.

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New insights into structural stability of SARS-CoV-2 main protease

New insights into structural stability of SARS-CoV-2 main protease

[ad_1] In a recent bioRxiv preprint paper, researchers from the US and Italy utilized molecular dynamics simulations and revealed that the conformational stability of the SARS-CoV-2 binding site, bound inhibitors, and the hydrogen bond networks of the viral main protease (Mpro) are highly sensitive to protonation assignments. [ad_2] Source link

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Win the fight against COVID-19

The search is on to find the perfect drug or vaccine to stop the spread of COVID-19. How can it be accomplished? The Department of Pharmaceutical Technology, Brainware University organised a webinar on “Protien Reliability Analysis and In Silico Modeling of Natural Inhibitors for SARS-CoV-2 Main Protease(Mpro): A Probable Solution for COVID-19” on 11 June 2020 to discuss the process of drug synthesis and diagnosis of this deadly infection. Our guest speaker Dr. Supratik Kar(Post Doctorate Research Associate, Interdisciplinary Center for Nanotoxicity, Jackson State University- MS,USA) discussed in details how computer aided drug designs, virtual screening, and other in-silico approaches are being used to find suitable drug testing candidates. Since we have at hand technology aided drug production is appreciably reducing production time and making it easier to look forward to a commercial COVID-19 drug. It will take some time yet but  advancements in pharmaceutical science have changed things for the better. Mr. Kar also advised students on the growing opportunities in the pharmaceutical field post-pandemic. It is expected that following the pandemic Government and corporate organisations will invest more in the health sector. That’s great news for the students who are looking to join the industry soon. The discussion ended with a Q &A session and was extremely useful for the students. We shall continue to provide such opportunities for our students to learn and grow.