New Thiophene-Derived α-aminophosphonic acids: Synthesis under microwave irradiations, antioxidant and antifungal activities, DFT investigations and SARS-CoV-2 main protease inhibition

The spread of SARS CoV 2 across the globe rushed the scientific community to find out the potential inhibitor for controlling the viral disease. The main protease (Mpro) or Chymotrypsin protease (3CLpro) is involved in the cleavage of polyproteins, duplication of intracellular materials and release of nonstructural proteins. Cys-His catalytic dyad is located in the SARS-CoV Mpro which is the substrate-binding site located in domains I and II. There are many approved drugs that have their active protease inhibition capability. The targeting of the active site of the main protease is the better option to fight against the viral population. Lopinavir, ritonavir, Remdesivir and Chloroquine are some of the drug candidates considered to be involved in the treatment of SARS CoV 2 under emergency situation as a trial basis. In the present investigation we used lopinavir as a drug to bind the catalytic dyad His41, Cys145 of main protease. The minimum binding of energy of -11.45 kcal/mol observed with the binding of Cys145 and -10.93 kcal/mol was noted with the residue His41. The inhibition constant was also found to be relevant to the binding efficiency of the drug. This is considered to be a model drug target which is initiating the finding of many new drugs to target the current outbreak created by the virus SARS.CoV - 2.

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Screening of Potent Phytochemical Inhibitors Against SARS-CoV-2 Main Protease: An Integrative Computational Approach

Frontiers in Bioinformatics ◽

10.3389/fbinf.2021.717141 ◽

2021 ◽

Vol 1 ◽

Author(s):

Shafi Mahmud ◽

Md. Robiul Hasan ◽

Suvro Biswas ◽

Gobindo Kumar Paul ◽

Shamima Afrose ◽

...

Keyword(s):

Root Mean Square ◽

Global Economy ◽

Transmission Rate ◽

Accessible Surface Area ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Mean Square ◽

Protease Inhibition ◽

Main Protease

Coronavirus disease 2019 (COVID-19) is a potentially lethal and devastating disease that has quickly become a public health threat worldwide. Due to its high transmission rate, many countries were forced to implement lockdown protocols, wreaking havoc on the global economy and the medical crisis. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus for COVID-19, represent an effective target for the development of a new drug/vaccine because it is well-conserved and plays a vital role in viral replication. Mpro inhibition can stop the replication, transcription as well as recombination of SARS-CoV-2 after the infection and thus can halt the formation of virus particles, making Mpro a viable therapeutic target. Here, we constructed a phytochemical dataset based on a rigorous literature review and explored the probability that various phytochemicals will bind with the main protease using a molecular docking approach. The top three hit compounds, medicagol, faradiol, and flavanthrin, had binding scores of −8.3, −8.6, and −8.8 kcal/mol, respectively, in the docking analysis. These three compounds bind to the active groove, consisting of His41, Cys45, Met165, Met49, Gln189, Thr24, and Thr190, resulting in main protease inhibition. Moreover, the multiple descriptors from the molecular dynamics simulation, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond analysis, confirmed the stable nature of the docked complexes. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis confirmed a lack of toxicity or carcinogenicity for the screened compounds. Our computational analysis may contribute toward the design of an effective drug against the main protease of SARS-CoV-2.

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Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir

Journal of General Virology ◽

10.1099/jgv.0.001625 ◽

2021 ◽

Vol 102 (7) ◽

Author(s):

Marie O. Pohl ◽

Idoia Busnadiego ◽

Francesco Marrafino ◽

Lars Wiedmer ◽

Annika Hunziker ◽

...

Keyword(s):

Protease Inhibitor ◽

Therapeutic Option ◽

Cell Entry ◽

Protease Inhibition ◽

Antiviral Compounds ◽

Main Protease ◽

Anti Cancer ◽

Synergistic Mechanism ◽

Host Cell Entry

Rapid repurposing of existing drugs as new therapeutics for COVID-19 has been an important strategy in the management of disease severity during the ongoing SARS-CoV-2 pandemic. Here, we used high-throughput docking to screen 6000 compounds within the DrugBank library for their potential to bind and inhibit the SARS-CoV-2 3 CL main protease, a chymotrypsin-like enzyme that is essential for viral replication. For 19 candidate hits, parallel in vitro fluorescence-based protease-inhibition assays and Vero-CCL81 cell-based SARS-CoV-2 replication-inhibition assays were performed. One hit, diclazuril (an investigational anti-protozoal compound), was validated as a SARS-CoV-2 3 CL main protease inhibitor in vitro (IC50 value of 29 µM) and modestly inhibited SARS-CoV-2 replication in Vero-CCL81 cells. Another hit, lenvatinib (approved for use in humans as an anti-cancer treatment), could not be validated as a SARS-CoV-2 3 CL main protease inhibitor in vitro, but serendipitously exhibited a striking functional synergy with the approved nucleoside analogue remdesivir to inhibit SARS-CoV-2 replication, albeit this was specific to Vero-CCL81 cells. Lenvatinib is a broadly-acting host receptor tyrosine kinase (RTK) inhibitor, but the synergistic effect with remdesivir was not observed with other approved RTK inhibitors (such as pazopanib or sunitinib), suggesting that the mechanism-of-action is independent of host RTKs. Furthermore, time-of-addition studies revealed that lenvatinib/remdesivir synergy probably targets SARS-CoV-2 replication subsequent to host-cell entry. Our work shows that combining computational and cellular screening is a means to identify existing drugs with repurposing potential as antiviral compounds. Future studies could be aimed at understanding and optimizing the lenvatinib/remdesivir synergistic mechanism as a therapeutic option.

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Studies on Computational Molecular Interaction Between SARS-CoV-2 Main Protease and Natural Products

10.26434/chemrxiv.12024789.v1 ◽

2020 ◽

Author(s):

Manish Manish

Keyword(s):

Natural Products ◽

Molecular Interaction ◽

Scientific Literature ◽

Dynamics Simulation ◽

Major Constituent ◽

Literature Mining ◽

Hydroxyl Groups ◽

Scoring Functions ◽

Protease Inhibition ◽

Main Protease

A combination of docking approaches, scoring functions, molecular dynamic simulation, and literature mining have been employed to screen readily available natural products (unique 27256 chemical entities, 598435 unique compounds), which can inhibit the SARS-CoV-2 main protease. Theaflavin digallate, a major constituent of black tea, has been observed to be as three top hits after the virtual screening of 598435 unique compounds. The main protease-theaflavin digallate complex appeared to be in the metastable stage and interact with critical active site residues of the main protease during molecular dynamics simulation for 200 ns. Invitro evidence on main protease inhibition of 2003 SARS-CoV by theaflavin digallate is available in the scientific literature. As evident by the dynamics of intermolecular interactions, theaflavin digallate, forms approximately three hydrogen bonds with Glu166 of main protease, mostly through hydroxyl groups in the benzene ring of benzo(7) annulen-6-one. Glu166 is the most critical amino acid for main protease dimerization, which in turn, is necessary for catalytic activity. We have employed chloroquine and epigallocatechin gallate (green tea component) as a control set. Based on computational molecular interaction and data available in scientific literature, theaflavin digallate can inhibit the main protease of SARS-CoV-2.

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Studies on Computational Molecular Interaction Between SARS-CoV-2 Main Protease and Natural Products

10.26434/chemrxiv.12024789.v2 ◽

2020 ◽

Cited By ~ 1

Author(s):

Manish Manish

Keyword(s):

Natural Products ◽

Molecular Interaction ◽

Scientific Literature ◽

Dynamics Simulation ◽

Major Constituent ◽

Literature Mining ◽

Hydroxyl Groups ◽

Scoring Functions ◽

Protease Inhibition ◽

Main Protease

A combination of docking approaches, scoring functions, molecular dynamic simulation, and literature mining have been employed to screen readily available natural products (unique 27256 chemical entities, 598435 unique compounds), which can inhibit the SARS-CoV-2 main protease. Theaflavin digallate, a major constituent of black tea, has been observed to be as three top hits after the virtual screening of 598435 unique compounds. The main protease-theaflavin digallate complex appeared to be in the metastable stage and interact with critical active site residues of the main protease during molecular dynamics simulation for 200 ns. Invitro evidence on main protease inhibition of 2003 SARS-CoV by theaflavin digallate is available in the scientific literature. As evident by the dynamics of intermolecular interactions, theaflavin digallate, forms approximately three hydrogen bonds with Glu166 of main protease, mostly through hydroxyl groups in the benzene ring of benzo(7) annulen-6-one. Glu166 is the most critical amino acid for main protease dimerization, which in turn, is necessary for catalytic activity. We have employed chloroquine and epigallocatechin gallate (green tea component) as a control set. Based on computational molecular interaction and data available in scientific literature, theaflavin digallate can inhibit the main protease of SARS-CoV-2.

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Studies on Computational Molecular Interaction Between SARS-CoV-2 Main Protease and Natural Products

10.26434/chemrxiv.12024789 ◽

2020 ◽

Author(s):

Manish Manish

Keyword(s):

Natural Products ◽

Molecular Interaction ◽

Scientific Literature ◽

Dynamics Simulation ◽

Major Constituent ◽

Literature Mining ◽

Hydroxyl Groups ◽

Scoring Functions ◽

Protease Inhibition ◽

Main Protease

A combination of docking approaches, scoring functions, molecular dynamic simulation, and literature mining have been employed to screen readily available natural products (unique 27256 chemical entities, 598435 unique compounds), which can inhibit the SARS-CoV-2 main protease. Theaflavin digallate, a major constituent of black tea, has been observed to be as three top hits after the virtual screening of 598435 unique compounds. The main protease-theaflavin digallate complex appeared to be in the metastable stage and interact with critical active site residues of the main protease during molecular dynamics simulation for 200 ns. Invitro evidence on main protease inhibition of 2003 SARS-CoV by theaflavin digallate is available in the scientific literature. As evident by the dynamics of intermolecular interactions, theaflavin digallate, forms approximately three hydrogen bonds with Glu166 of main protease, mostly through hydroxyl groups in the benzene ring of benzo(7) annulen-6-one. Glu166 is the most critical amino acid for main protease dimerization, which in turn, is necessary for catalytic activity. We have employed chloroquine and epigallocatechin gallate (green tea component) as a control set. Based on computational molecular interaction and data available in scientific literature, theaflavin digallate can inhibit the main protease of SARS-CoV-2.

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Using serpins cysteine protease cross-specificity to possibly trap SARS-CoV-2 Mpro with reactive center loop chimera

Clinical Science ◽

10.1042/cs20200767 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2235-2241

Author(s):

Mohamad Aman Jairajpuri ◽

Shoyab Ansari

Keyword(s):

Cysteine Protease ◽

Active Site ◽

Cleavage Site ◽

Serine Proteases ◽

Therapeutic Potential ◽

Cysteine Proteases ◽

Protease Inhibition ◽

Reactive Center Loop ◽

Main Protease ◽

Reactive Center

Abstract Human serine protease inhibitors (serpins) are the main inhibitors of serine proteases, but some of them also have the capability to effectively inhibit cysteine proteases. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) main protease (Mpro) is a chymotrypsin-type cysteine protease that is needed to produce functional proteins essential for virus replication and transcription. Serpin traps its target proteases by presenting a reactive center loop (RCL) as protease-specific cleavage site, resulting in protease inactivation. Mpro target sites with its active site serine and other flanking residues can possibly interact with serpins. Alternatively, RCL cleavage site of serpins with known evidence of inhibition of cysteine proteases can be replaced by Mpro target site to make chimeric proteins. Purified chimeric serpin can possibly inhibit Mpro that can be assessed indirectly by observing the decrease in ability of Mpro to cleave its chromogenic substrate. Chimeric serpins with best interaction and active site binding and with ability to form 1:1 serpin–Mpro complex in human plasma can be assessed by using SDS/PAGE and Western blot analysis with serpin antibody. Trapping SARS-CoV-2 Mpro cysteine protease using cross-class serpin cysteine protease inhibition activity is a novel idea with significant therapeutic potential.

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A Microscopic Description of SARS-CoV-2 Main Protease Inhibition with Michael Acceptors. Strategies for Improving Inhibitors Design

10.26434/chemrxiv.12895064 ◽

2020 ◽

Author(s):

Carlos A. Ramos-Guzmán ◽

J. Javier Ruiz-Pernía ◽

Iñaki Tuñón

Keyword(s):

Free Energy ◽

Enzyme Inhibitor ◽

Multiscale Simulation ◽

Ion Pair ◽

Protease Inhibition ◽

Microscopic Description ◽

Inhibitor Complex ◽

Main Protease ◽

Michael Acceptors ◽

Catalytic Dyad

The irreversible inhibition of the main protease of SARS-CoV-2 by a Michael acceptor compound known as N3 has been investigated using multiscale simulation methods. The noncovalent enzyme-inhibitor complex was simulated using classical Molecular Dynamics techniques and the pose of the inhibitor in the active site was compared to that of the natural substrate, a peptide containing the Gln-Ser scissile bond. The formation of the covalent enzyme-inhibitor complex was then simulated using hybrid QM/MM free energy methods. After binding, the reaction mechanism was found to be composed of two steps: i) the activation of the catalytic dyad (Cys145 and His41) to form an ion pair and ii) a Michael addition where the attack of the Sg atom of Cys145 to the Cb atom of the inhibitor precedes the water-mediated proton transfer from His41 to the Ca atom. The microscopic description of protease inhibition by N3 obtained from our simulations is strongly supported by the excellent agreement between the estimated activation free energy and the value derived from kinetic experiments. Comparison with the acylation reaction of a peptide substrate suggest that that N3-based inhibitors could be improving adding chemical modifications that could facilitate the formation of the catalytic dyad ion pair.

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Favipiravir May Acts as COVID-19 Main Protease PDB ID 6LU7 Inhibitor: Docking Analysis

Biointerface Research in Applied Chemistry ◽

10.33263/briac106.68216828 ◽

2020 ◽

Vol 10 (6) ◽

pp. 6821-6828 ◽

Cited By ~ 2

Keyword(s):

Amino Acids ◽

Protease Inhibitor ◽

Essential Amino Acids ◽

Antiviral Drugs ◽

Binding Pattern ◽

Protease Inhibition ◽

Docking Analysis ◽

Protease Enzyme ◽

Main Protease ◽

Polymerase Inhibitor

Coronavirus is a well-known threat to the human being in the form of COVID-19. Virus replication may be controlled by inhibition of protease enzyme. Hence, well known 13 antiviral drugs have been observed by docking analysis for understanding the binding pattern of drugs with COVID-19 main protease PDB ID: 6LU7 for any possibilities of protease inhibition. For docking analysis PyRx- Python Prescription 0.8 was used. This analysis reveals that the essential amino acids involved in binding of antiviral drugs to COVID-19 main protease PDB ID: 6LU7 are Glycine (Gly), Serine (Ser), Cysteine (Cys), Leucine (Leu), Asparagine (Asn), Glutamine (Gln), Glutamic acid (Glu) and Threonine (Thr). After docking analysis, it was observed that Favipiravir maybe act as COVID-19 main protease inhibitor despite being vRNA polymerase inhibitor and may further be used in the treatment of COVID-19 infection.

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