Crystal structures of human coronavirus NL63 main protease at different pH values

2021 ◽  
Vol 77 (10) ◽  
Author(s):  
Hongxia Gao ◽  
Yuting Zhang ◽  
Haihai Jiang ◽  
Xiaohui Hu ◽  
Yuting Zhang ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Drug Target ◽  
Clinical Manifestations ◽  
Structural Features ◽  
Vital Role ◽  
Human Coronavirus ◽  
Respiratory Illnesses ◽  
Ph Values ◽  
Main Protease ◽  
Etiological Agents

Human coronavirus NL63 (HCoV-NL63), which belongs to the genus Alphacoronavirus, mainly infects children and the immunocompromized and is responsible for a series of clinical manifestations, including cough, fever, rhinorrhoea, bronchiolitis and croup. HCoV-NL63, which was first isolated from a seven-month-old child in 2004, has led to infections worldwide and accounts for 10% of all respiratory illnesses caused by etiological agents. However, effective antivirals against HCoV-NL63 infection are currently unavailable. The HCoV-NL63 main protease (Mpro), also called 3C-like protease (3CLpro), plays a vital role in mediating viral replication and transcription by catalyzing the cleavage of replicase polyproteins (pp1a and pp1ab) into functional subunits. Moreover, Mpro is highly conserved among all coronaviruses, thus making it a prominent drug target for antiviral therapy. Here, four crystal structures of HCoV-NL63 Mpro in the apo form at different pH values are reported at resolutions of up to 1.78 Å. Comparison with Mpro from other human betacoronaviruses such as SARS-CoV-2 and SARS-CoV reveals common and distinct structural features in different genera and extends knowledge of the diversity, function and evolution of coronaviruses.

scholarly journals Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Wayne Vuong ◽  
Muhammad Bashir Khan ◽  
Conrad Fischer ◽  
Elena Arutyunova ◽  
Tess Lamer ◽  
...  
Keyword(s):  
Drug Target ◽  
Covalent Modification ◽  
Human Coronavirus ◽  
Feline Infectious Peritonitis ◽  
Drug Candidates ◽  
Main Protease ◽  
Coronavirus Infection ◽  
Reversible Formation ◽  
Nanomolar Range ◽  
Feline Coronavirus

Abstract The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.

Prevention of SARS-CoV-2 Proliferation with a Novel and Potent Main Protease Inhibitor by Docking, ADMET, MM-PBSA, and Molecular Dynamics Simulation

2021 ◽  
pp. 2150014
Author(s):  
Akbar Noorbakhsh ◽  
Rafee Habib Askandar ◽  
Mohammad Shakib Alhagh ◽  
Chiako Farshadfar ◽  
Seyed Hamid Seyedi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Target ◽  
Md Simulation ◽  
Vital Role ◽  
Lung Damage ◽  
Dynamics Simulation ◽  
Reference Drug ◽  
Main Protease ◽  
Poisson Boltzmann ◽  
Adme Properties

COVID-19 is the last disease caused by SARS-CoV-2 associated with a severe immune response and lung damage. The main protease (Mpro) has a vital role in SARS-CoV-2 proliferation. Moreover, humans lack homologous Mpro, which makes the Mpro a suitable drug target for the development of SARS-CoV-2 drugs. The purchasable L5000 library (Selleckchem Inc) includes 99,040 compounds that were used for virtual screening. After molecular docking and ADME studies, we selected a compound (WAY-604395) with a potent binding affinity to the Mpro active site and acceptable ADME properties compared to the reference drug (nelfinavir). Molecular dynamics (MD) simulation outcomes have proved that the Mpro-WAY604395 complex possesses a considerable value of flexibility, stability, compactness and binding energy. Our Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculation demonstrates that WAY-604395 is more potent ([Formula: see text]272.19[Formula: see text]kcal mol[Formula: see text]) in comparison with nelfinavir ([Formula: see text]173.39[Formula: see text]kcal[Formula: see text]mol[Formula: see text]) against SARS-CoV-2 Mpro. In conclusion, we suggest that WAY-604395 has the potential for the treatment of SARS-CoV-2 by inhibition of the Mpro.

scholarly journals Genetic Algorithm-Based Docking of Potent Inhibitors Against SARS-CoV-2 Main Protease: A Comparison Between Natural Products and Synthetic Drugs.

2020 ◽  
Author(s):  
Pragadeeshwara Rao R ◽  
Tinku Basu
Keyword(s):  
Genetic Algorithm ◽  
Natural Products ◽  
Severe Acute Respiratory Syndrome ◽  
Betulinic Acid ◽  
Drug Target ◽  
Vital Role ◽  
Intensive Research ◽  
Synthetic Drugs ◽  
Main Protease ◽  
Potential Inhibitors

<p>The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused coronavirus disease-2019 (COVID-19) pandemic. Despite the intensive research currently, there are no therapeutics and vaccines available. As the main protease (M<sup>Pro</sup>) plays a vital role in SARS-CoV-2, it is an attractive drug target. Herein we report, potential inhibitors form natural products and synthetic drugs against M<sup>Pro</sup>. In detail, we studied the interaction of inhibitors (Curcumin, Theaflavin, Deserpidine, Betulinic acid, Sinigrin, Emodin, Leptodactylone, Synthetic drugs, Lopinavir, Ritonavir, Indinavir, Amprenavir, Darunavir, Nelfinavir, Remdesivir, Saquinavir, Sivelestat, Galidesivir, and Favipiravir) with the catalytic site of M<sup>Pro</sup>. Lastly, ADME (Absorption, Distribution, Metabolism, and Excretion) properties of Natural products and synthetic drugs are explored. We identified eight potential inhibitors against M<sup>Pro</sup>. <b></b></p>

scholarly journals Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

2020 ◽  
Author(s):  
Wayne Vuong ◽  
Muhammad Bashir Khan ◽  
Conrad Fischer ◽  
Elena Arutyunova ◽  
Tess Lamer ◽  
...  
Keyword(s):  
Drug Target ◽  
Covalent Modification ◽  
Human Coronavirus ◽  
Feline Infectious Peritonitis ◽  
Drug Candidates ◽  
Main Protease ◽  
Coronavirus Infection ◽  
Reversible Formation ◽  
Nanomolar Range ◽  
Feline Coronavirus

AbstractThe COVID-19 pandemic, attributed to the SARS-CoV-2 coronavirus infection, resulted in millions infected worldwide and an immediate need for antiviral treatments. The main protease (Mpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide and subsequent viral replication. Feline infectious peritonitis, a fatal infection in cats caused by a coronavirus, was successfully treated previously with a dipeptide-based protease inhibitor. Here we show this drug, GC376, and its analog GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of the SARS-CoV and SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 in cell culture, with EC50 values near one micromolar and little to no toxicity. These protease inhibitors are soluble, non-toxic, and bind reversibly. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals (cats). The work here lays the framework for their use in human trials for the treatment of COVID-19.

scholarly journals The Possible Molecular Mechanism of SARS-CoV-2 Main Protease: New Structural Insights from Computational Methods

2021 ◽  
Vol 2 ◽  
pp. 108-126
Author(s):  
Alvea Tasneem ◽  
Gyan Prakash Rai ◽  
Saima Reyaz ◽  
Hridoy R. Bairagya
Keyword(s):  
Drug Target ◽  
Computational Study ◽  
Vital Role ◽  
Testable Hypothesis ◽  
Water Molecules ◽  
Main Protease ◽  
Definition Of ◽  
Imidazolium Ion ◽  
Catalytic Dyad ◽  
Structural Insights

Main protease (Mpro) is one of the key enzymes in the life cycle of SARS-CoV-2 that plays a pivotal role in mediating viral replication, transcription, and makes it an attractive drug target for this virus.  The catalytic site of this enzyme comprises of a dyad His41 and Cys145 and lacks the third catalytic residue, which is replaced by a stable water molecule (W). The computational structural analysis on crystal data for Mpro protein suggests that W1, W2, His163, and Tyr161 may also play a vital role in the activity of this enzyme and they may act as catalytic partners along with Cys(145)-His(41) catalytic dyad. The thiolate–imidazolium ion-pair between Cys145 (-SH---NE2-) His41 and Cys145 (-SH---NE2-) His163 have been stabilized by W1 (with W2) and Tyr161, respectively. Therefore, unique interactions of W2---W1---ND1-His41-NE2---SH-Cys145 or Cys145-SH---NE2-His163-ND1---OH-Tyr161 in Mpro serve as an excellent drug target for this enzyme and suggest a rethink of the conventional definition of chemical geometry of inhibitor binding site, its shape, and complementarities. Our computational hypothesis suggests two essential clues that may be implemented to design a new inhibitor for Mpro protein. The strategies are: (i) ligand should be occupied either W1 or W2 or both of these position to displace these water molecules from the catalytic region, and (ii) ligand should be made H-bonds with Cys145 (-SH), His41 (NE2/ND1) and His163(NE2) to inhibit Mpro. The results from this computational study could be of interest to the experimental community and also provide a testable hypothesis for experimental validation. Doi: 10.28991/SciMedJ-2020-02-SI-11 Full Text: PDF

scholarly journals Genetic Algorithm-Based Docking of Potent Inhibitors Against SARS-CoV-2 Main Protease: A Comparison Between Natural Products and Synthetic Drugs.

2020 ◽  
Author(s):  
Pragadeeshwara Rao R ◽  
Tinku Basu
Keyword(s):  
Genetic Algorithm ◽  
Natural Products ◽  
Severe Acute Respiratory Syndrome ◽  
Betulinic Acid ◽  
Drug Target ◽  
Vital Role ◽  
Intensive Research ◽  
Synthetic Drugs ◽  
Main Protease ◽  
Potential Inhibitors

<p>The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused coronavirus disease-2019 (COVID-19) pandemic. Despite the intensive research currently, there are no therapeutics and vaccines available. As the main protease (M<sup>Pro</sup>) plays a vital role in SARS-CoV-2, it is an attractive drug target. Herein we report, potential inhibitors form natural products and synthetic drugs against M<sup>Pro</sup>. In detail, we studied the interaction of inhibitors (Curcumin, Theaflavin, Deserpidine, Betulinic acid, Sinigrin, Emodin, Leptodactylone, Synthetic drugs, Lopinavir, Ritonavir, Indinavir, Amprenavir, Darunavir, Nelfinavir, Remdesivir, Saquinavir, Sivelestat, Galidesivir, and Favipiravir) with the catalytic site of M<sup>Pro</sup>. Lastly, ADME (Absorption, Distribution, Metabolism, and Excretion) properties of Natural products and synthetic drugs are explored. We identified eight potential inhibitors against M<sup>Pro</sup>. <b></b></p>

scholarly journals The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lucia Silvestrini ◽  
Norhan Belhaj ◽  
Lucia Comez ◽  
Yuri Gerelli ◽  
Antonino Lauria ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Dissociation Constant ◽  
Molecular Mechanisms ◽  
Antiviral Drug ◽  
Structural Features ◽  
Experimental Information ◽  
Detailed Knowledge ◽  
Main Protease ◽  
Equilibrium Dissociation ◽  
Drug Leads

AbstractThe maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.

scholarly journals The Potency of Seaweed Sulfated Polysaccharides for the Correction of Hemostasis Disorders in COVID-19

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2618
Author(s):  
Tatyana A. Kuznetsova ◽  
Boris G. Andryukov ◽  
Ilona D. Makarenkova ◽  
Tatyana S. Zaporozhets ◽  
Natalya N. Besednova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Therapeutic Potential ◽  
Low Cost ◽  
Clinical Manifestations ◽  
Optimal Dose ◽  
Monosaccharide Composition ◽  
Structural Features ◽  
Sulfated Polysaccharides ◽  
Clinical Use ◽  
Hemostasis System

Hemostasis disorders play an important role in the pathogenesis, clinical manifestations, and outcome of COVID-19. First of all, the hemostasis system suffers due to a complicated and severe course of COVID-19. A significant number of COVID-19 patients develop signs of hypercoagulability, thrombocytopenia, and hyperfibrinolysis. Patients with severe COVID-19 have a tendency toward thrombotic complications in the venous and arterial systems, which is the leading cause of death in this disease. Despite the success achieved in the treatment of SARS-CoV-2, the search for new effective anticoagulants, thrombolytics, and fibrinolytics, as well as their optimal dose strategies, continues to be relevant. The wide therapeutic potential of seaweed sulfated polysaccharides (PSs), including anticoagulant, thrombolytic, and fibrinolytic activities, opens up new possibilities for their study in experimental and clinical trials. These natural compounds can be important complementary drugs for the recovery from hemostasis disorders due to their natural origin, safety, and low cost compared to synthetic drugs. In this review, the authors analyze possible pathophysiological mechanisms involved in the hemostasis disorders observed in the pathological progression of COVID-19, and also focus the attention of researchers on seaweed PSs as potential drugs aimed to correction these disorders in COVID-19 patients. Modern literature data on the anticoagulant, antithrombotic, and fibrinolytic activities of seaweed PSs are presented, depending on their structural features (content and position of sulfate groups on the main chain of PSs, molecular weight, monosaccharide composition and type of glycosidic bonds, the degree of PS chain branching, etc.). The mechanisms of PS action on the hemostasis system and the issues of oral bioavailability of PSs, important for their clinical use as oral anticoagulant and antithrombotic agents, are considered. The combination of the anticoagulant, thrombolytic, and fibrinolytic properties, along with low toxicity and relative cheapness of production, open up prospects for the clinical use of PSs as alternative sources of new anticoagulant and antithrombotic compounds. However, further investigation and clinical trials are needed to confirm their efficacy.

The Gold Sulfates MAu(S04)2 (M = Na, K, Rb)

2001 ◽  
Vol 56 (12) ◽  
pp. 1340-1343 ◽  
Author(s):  
Mathias S. Wickleder ◽  
Oliver Büchner
Keyword(s):  
Sulfuric Acid ◽  
Single Crystals ◽  
Crystal Structures ◽  
Structural Features ◽  
Monovalent Cations ◽  
Coordination Numbers ◽  
Square Planar ◽  
Oxygen Atoms

AbstractThe evaporation of a solution of Au(OH)3 and Na2So4 in conc. sulfuric acid led to yellow single crystals of NaAu(SO4)2 (monoclinic, P21/n, Z = 2, a = 469.1, b = 845.9, c = 831.2 pm, β = 95.7°). Analogous procedures with K2SO4 or Rb2SO4 instead of Na2SO4 yielded single crystals of KAu(SO4)2 (monoclinic, C2/c, Z = 4, a = 1109.8, b = 724.2, c = 941.1 pm, β = 118.4°) and RbAu(S04)2, respectively, (triclinic, P1̄, Z = 1, a = 423.6, b = 497.5, c = 889.0 pm, a = 76.4°, β = 88.4°, γ = 73.5°). Although the crystal structures of the three sulfates are not isotypic they show similar structural features: The gold atoms are coordinated by four oxygen atoms in a square planar manner. These oxygen atoms belong to four SO42- ions which link the [AUO4] units to infinite chains according to 1∞[Au(SO4)4/ 2]- . These chains are connected via the monovalent cations which show coordination numbers of 6 (Na+), 10 (K+) and 12 (Rb+), respectively.

Clinical Management Updates for Novel Corona Virus (COVID-19)

2021 ◽  
Vol 14 (3) ◽  
pp. 5449-5456
Author(s):  
Yogesh Chand Yadav ◽  
Ramakant Yadav ◽  
Sushant Kumar
Keyword(s):  
Clinical Management ◽  
Respiratory Illness ◽  
Symptomatic Treatment ◽  
Structural Features ◽  
Therapeutic Agents ◽  
Human Coronavirus ◽  
Transmission Potential ◽  
The World ◽  
Severe Respiratory Illness ◽  
Droplet Transmission

The SARS-CoV-2 virus was first detected in Wuhan, China in December 2019 and was known to produce acute severe respiratory illness in humans which rapidly spread almost throughout the world within a few months. This human coronavirus has seven strains and they commonly produce illness in the nervous system, respiratory system and hepato- intestinal systems. This present review is an attempt to illustrate recent reports pertaining to the management of SARS-CoV-2. Further, it also highlights the diagnosis and clinical management of COVID-19. Various search engines like Scopus, Pubmed and WHO databases were accessed and literature on current advances about COVID-19 including structural features, replication, possible pathogenic, symptoms, diagnosis, prognosis, methods of prevention and possible therapeutic agents used for treatment of patients was reviewed. Current studies indicate that COVID-19 is very infectious with droplet transmission potential. The key modalities to prevent the infection is by keeping social distancing, respiratory/hand hygiene, detection of infection and subsequent quarantine of the infected persons. Presently, either no vaccine for prevention or specific treatments available, however, COVID-19 patients may be managed by using some repositioned drugs and symptomatic treatment.

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