A Potential Peptide From Soy Cheese Produced Using Lactobacillus delbrueckii WS4 for Effective Inhibition of SARS-CoV-2 Main Protease and S1 Glycoprotein

The COVID-19 pandemic caused by novel SARS-CoV-2 has resulted in an unprecedented loss of lives and economy around the world. In this study, search for potential inhibitors against two of the best characterized SARS-CoV-2 drug targets: S1 glycoprotein receptor-binding domain (RBD) and main protease (3CLPro), was carried out using the soy cheese peptides. A total of 1,420 peptides identified from the cheese peptidome produced using Lactobacillus delbrueckii WS4 were screened for antiviral activity by employing the web tools, AVPpred, and meta-iAVP. Molecular docking studies of the selected peptides revealed one potential peptide “KFVPKQPNMIL” that demonstrated strong affinity toward significant amino acid residues responsible for the host cell entry (RBD) and multiplication (3CLpro) of SARS-CoV-2. The peptide was also assessed for its ability to interact with the critical residues of S1 RBD and 3CLpro of other β-coronaviruses. High binding affinity was observed toward critical amino acids of both the targeted proteins in SARS-CoV, MERS-CoV, and HCoV-HKU1. The binding energy of KFVPKQPNMIL against RBD and 3CLpro of the four viruses ranged from −8.45 to −26.8 kcal/mol and −15.22 to −22.85 kcal/mol, respectively. The findings conclude that cheese, produced by using Lb. delbrueckii WS4, could be explored as a prophylactic food for SARS-CoV-2 and related viruses. In addition, the multi-target inhibitor peptide, which effectively inhibited both the viral proteins, could further be used as a terminus a quo for the in vitro and in vivo function against SARS-CoV-2.

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An In-Silico Study on Selected Organosulfur Compounds as Potential Drugs for SARS-CoV-2 Infection via Binding Multiple Drug Targets

10.26434/chemrxiv.12505343 ◽

2020 ◽

Author(s):

Liya Thurakkal ◽

Satyam Singh ◽

Sushabhan Sadhukhan ◽

Mintu Porel

Keyword(s):

Drug Targets ◽

Target Prediction ◽

Multiple Drug ◽

Organosulfur Compounds ◽

Potential Candidate ◽

Health Crisis ◽

Drug Molecules ◽

Main Protease

The emerging paradigm shift from ‘one molecule, one target, for one disease’ towards ‘multi-targeted small molecules’ has paved an ingenious pathway in drug discovery in recent years. This idea has been extracted for the investigation of competent drug molecules for the unprecedented COVID-19 pandemic which became the greatest global health crisis now. Perceiving the importance of organosulfur compounds against SARS-CoV-2 from the drugs under clinical trials, a class of organosulfur compounds effective against SARS-CoV were selected and studied the interaction with multiple proteins of the SARS-CoV-2. One compound displayed inhibition against five proteins (both structural and non-structural) of the virus namely, main protease, papain-like protease, spike protein, helicase and RNA dependent RNA polymerase. Consequently, this compound emanates as a potential candidate for treating the virulent disease. The pharmacokinetics, ADMET properties and target prediction studies carried out in this work further inflamed the versatility of the compound and urge to execute in-vitro and in-vivo analysis on SARS-CoV-2 in the future.

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Virtual Screening of Potential Inhibitors for SARS-CoV-2 Main Protease

10.20944/preprints202004.0146.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Carlos Javier Alméciga-Díaz ◽

Luisa N. Pimentel-Vera ◽

Angela Caro ◽

Angela Mosquera ◽

Camilo Andrés Castellanos Moreno ◽

...

Keyword(s):

Virtual Screening ◽

Clinical Information ◽

Virus Genome ◽

Pharmacological Agents ◽

Main Protease ◽

Novel Coronavirus ◽

Approved Drugs ◽

Potential Inhibitors

Coronavirus Disease 2019 (Covid-19) was first described in December 2019 in Wuhan, Hubei Province, China; and produced by a novel coronavirus designed as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 has become a pandemic reaching over 1.3 million confirmed cases and 73,000 deaths. Several efforts have been done to identify pharmacological agents that can be used to treat patients and protect healthcare professionals. The sequencing of the virus genome not only has offered the possibility to develop a vaccine, but also to identified and characterize the virus proteins. Among these proteins, main protease (Mpro) has been identified as a potential therapeutic target, since it is essential for the processing other viral proteins. Crystal structures of SARS-CoV-2 Mpro and inhibitors has been described during the last months. To describe additional compounds that can inhibit SARS-CoV-2 Mpro, in this study we performed a molecular docking-based virtual screening against a library of experimental and approved drugs. Top 10 hits included Pictilisib, Nimorazole, Ergoloid mesylates, Lumacaftor, Cefuroxime, Cepharanhine, and Nilotinib. These compounds were predicted to have higher binding affinity for SARS-CoV-2 Mpro than previously reported inhibitors for this protein, suggesting a higher potential to inhibit virus replication. Since the identified drugs have both pre-clinical and clinical information, we consider that these results may contribute to the identification of treatment alternative for Covid-19. Nevertheless, in vitro and in vivo confirmation should be performed before these compounds could be translated to the clinic.

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Potential Bioactive glycosylated flavonoids as SARS-CoV-2 Main protease Inhibitors: A molecular Docking Study

10.31219/osf.io/k4h5f ◽

2020 ◽

Author(s):

sabri ahmed cherrak ◽

merzouk hafida ◽

mokhtari soulimane nassima

Keyword(s):

Molecular Docking ◽

Data Bank ◽

Docking Study ◽

Docking Studies ◽

Molecular Docking Study ◽

Chemical Structures ◽

In Vivo Experiments ◽

Main Protease

A novel (COVID-19) responsible of acute respiratory infection closely related to SARS-CoV has recently emerged. So far there is no consensus for drug treatment to stop the spread of the virus. Discovery of a drug that would limit the virus expansion is one of the biggest challenges faced by the humanity in the last decades. In this perspective, testing existing drugs as inhibitors of the main COVID-19 protease is a good approach.Among natural phenolic compounds found in plants, fruit, and vegetables; flavonoids are the most abundant. Flavonoids, especially in their glycosylated forms, display a number of physiological activities, which makes them interesting to investigate as antiviral molecules.The flavonoids chemical structures were downloaded from PubChem and protease structure 6lu7 was from the Protein Data Bank site. Molecular docking study was performed using AutoDock Vina. Among the tested molecules Quercetin-3-O-rhamnoside showed the highest binding affinity (-9,7 kcal/mol). Docking studies showed that glycosylated flavonoids are good inhibitors for the covid-19 protease and could be further investigated by in vitro and in vivo experiments for further validation.

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An Evaluation of 3-Rhamnosylquercetin, a Glycosylated Form of Quercetin, against the Myotoxic and Edematogenic Effects of sPLA2fromCrotalus durissus terrificus

BioMed Research International ◽

10.1155/2014/341270 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Daniela de Oliveira Toyama ◽

Henrique Hessel Gaeta ◽

Marcus Vinícius Terashima de Pinho ◽

Marcelo José Pena Ferreira ◽

Paulete Romoff ◽

...

Keyword(s):

Amino Acid ◽

Docking Studies ◽

Pharmacological Effects ◽

Amino Acid Residues ◽

Substrate Molecule ◽

Pharmacological Activities ◽

Potent Inhibition ◽

Crotalus Durissus

This paper shows the results of quercitrin effects on the structure and biological activity of secretory phospholipase (sPLA2) fromCrotalus durissus terrificus, which is the main toxin involved in the pharmacological effects of this snake venom. According to our mass spectrometry and circular dichroism results, quercetin was able to promote a chemical modification of some amino acid residues and modify the secondary structure ofC. d. terrificussPLA2. Moreover, molecular docking studies showed that quercitrin can establish chemical interactions with some of the crucial amino acid residues involved in the enzymatic activity of the sPLA2, indicating that this flavonoid could also physically impair substrate molecule access to the catalytic site of the toxin. Additionally,in vitroandin vivoassays showed that the quercitrin strongly diminished the catalytic activity of the protein, altered its Vmax and Km values, and presented a more potent inhibition of essential pharmacological activities in theC. d. terrificussPLA2, such as its myotoxicity and edematogenic effect, in comparison to quercetin. Thus, we concluded that the rhamnose group found in quercitrin is most likely essential to the antivenom activities of this flavonoid againstC. d. terrificussPLA2.

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Flexibility and mobility of SARS-CoV-2-related protein structures

Scientific Reports ◽

10.1038/s41598-021-82849-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rudolf A. Römer ◽

Navodya S. Römer ◽

A. Katrine Wallis

Keyword(s):

In Silico ◽

Drug Targets ◽

Large Scale ◽

Structural Information ◽

Protein Structures ◽

Antiviral Drug ◽

Docking Studies ◽

Related Protein

AbstractThe worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible. Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico. Here, we are using in silico modelling of possible SARS-CoV-2 drug targets, as deposited on the Protein Databank (PDB), and ascertain their dynamics, flexibility and rigidity. For example, for the SARS-CoV-2 spike protein—using its complete homo-trimer configuration with 2905 residues—our method identifies a large-scale opening and closing of the S1 subunit through movement of the S$${}^\text{B}$$ B domain. We compute the full structural information of this process, allowing for docking studies with possible drug structures. In a dedicated database, we present similarly detailed results for the further, nearly 300, thus far resolved SARS-CoV-2-related protein structures in the PDB.

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Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

Pharmaceutics ◽

10.3390/pharmaceutics14010010 ◽

2021 ◽

Vol 14 (1) ◽

pp. 10

Author(s):

Carla S. S. Teixeira ◽

Sérgio F. Sousa

Keyword(s):

Posttranslational Modifications ◽

Drug Targets ◽

Current Status ◽

Cancer Drug ◽

Cancer Cell Growth ◽

Anti Cancer ◽

Multifunctional Enzymes ◽

Potential Inhibitors

Fighting cancer is one of the major challenges of the 21st century. Among recently proposed treatments, molecular-targeted therapies are attracting particular attention. The potential targets of such therapies include a group of enzymes that possess the capability to catalyze at least two different reactions, so-called multifunctional enzymes. The features of such enzymes can be used to good advantage in the development of potent selective inhibitors. This review discusses the potential of multifunctional enzymes as anti-cancer drug targets along with the current status of research into four enzymes which by their inhibition have already demonstrated promising anti-cancer effects in vivo, in vitro, or both. These are PFK-2/FBPase-2 (involved in glucose homeostasis), ATIC (involved in purine biosynthesis), LTA4H (involved in the inflammation process) and Jmjd6 (involved in histone and non-histone posttranslational modifications). Currently, only LTA4H and PFK-2/FBPase-2 have inhibitors in active clinical development. However, there are several studies proposing potential inhibitors targeting these four enzymes that, when used alone or in association with other drugs, may provide new alternatives for preventing cancer cell growth and proliferation and increasing the life expectancy of patients.

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Curcumins and its derivatives as potential inhibitors of New Coronavirus (COVID-19) main protease: an in silico strategy

Research Society and Development ◽

10.33448/rsd-v11i1.24334 ◽

2022 ◽

Vol 11 (1) ◽

pp. e6511124334

Author(s):

Daniela Ribeiro Alves ◽

Matheus Nunes da Rocha ◽

Camila Caldas Oliveira Passos ◽

Márcia Machado Marinho ◽

Emmanuel Silva Marinho ◽

...

Keyword(s):

Biological Activities ◽

Specific Treatment ◽

Bioactive Molecules ◽

Curcumin Derivatives ◽

Main Protease ◽

Protein Receptors ◽

Future Evaluation ◽

Potential Inhibitors

Coronavirus (COVID-19) disease outbreak caused a worldwide pandemic with a powerful lethal potential and still, there is no specific treatment to it. Natural bioactive molecules like curcumins were investigated in this work aiming to block the active site of COVID-19 Main protease (Mpro), since they present several biological activities, being more suitable in terms of fewer side effects, once this disease overloads the immune system of patients. Hereby, curcumin and several derivatives were screened for their ability to react with Mpro receptors (PDB: 6LU7). N3, Azithromycin (AZT), and Baracitinib (BRT) were evaluated as positive controls and in combined therapeutics possibilities with curcumins. N3, AZT, and BRT bound to different protein receptors, and also it was observed that N3 bound in the same site as hexahydrocurcumin and curcumin glucuronide bound at the AZT’s site and bisdemethoxycurcumin, curcumin, curcumin sulfate, cyclocurcumin, demethoxycurcumin, dihydrocurcumin and hexahydrocurcuminol bound at BRT’s site. All molecules analyzed have high force interaction fields. Once the viral activity is mainly intracellular, these compounds also were evaluated for their hydropathic abilities. All molecules were classified and considered capable of membrane cell invading. These results suggest that the therapeutic approach of the curcumin derivatives associated with AZT and the antiviral inhibitor N3 is promissory for future evaluation of their synergism in in vitro and in vivo tests to define their additional viability in the treatment of COVID-19.

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In Silico Screening of Naturally Occurring Coumarin Derivatives for the Inhibition of the Main Protease of SARS-CoV-2

10.26434/chemrxiv.12234728 ◽

2020 ◽

Author(s):

Sona Lyndem ◽

Sharat Sarmah ◽

Sourav Das ◽

Atanu Singha Roy

Keyword(s):

Active Site ◽

Preliminary Screening ◽

Naturally Occurring ◽

Main Protease ◽

Coumarin Compounds ◽

Potential Inhibitors ◽

Novel Drug ◽

Catalytic Dyad

The dissemination of a novel corona virus, SARS-CoV-2, through rapid human to human transmission has led to a global health emergency. The lack of a vaccine or medication for effective treatment of this disease has made it imperative for developing novel drug discovery approaches. Repurposing of drugs is one such method currently being used to tackle the viral infection. The genome of SARS-CoV-2 replicates due to the functioning of a main protease called Mpro. By targeting the active site of Mpro with potential inhibitors, this could prevent viral replication from taking place. Blind docking technique was used to investigate the interactions between 29 naturally occurring coumarin compounds and SARS-CoV-2 main protease, Mpro, out of which 17 coumarin compounds were seen to bind to the active site through the interaction with the catalytic dyad, His41 and Cys145, along with other neighbouring residues. On comparing the ΔG values of the coumarins bound to the active site of Mpro, corymbocoumarin belonging to the class pyranocoumarins, methylgalbanate belonging to the class simple coumarins and heraclenol belonging to the class furanocoumarins, displayed best binding efficiency and could be considered as potential Mpro protease inhibitors. Preliminary screening of these naturally occurring coumarin compounds as potential SARS-CoV-2 replication inhibitors acts as a stepping stone for further in vitro and in vivo experimental investigation and analytical validation.

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Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro) Identified from the Library of FDA Approved Drugs Using Molecular Docking Studies

10.20944/preprints202004.0149.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Dipesh Verma ◽

Srajan Kapoor ◽

Satyajeet Das ◽

Krishan Thakur

Keyword(s):

Molecular Docking ◽

Therapeutic Potential ◽

Docking Studies ◽

Antiviral Compound ◽

Molecular Docking Studies ◽

Main Protease ◽

Approved Drugs ◽

Fda Approved Drugs

Corona Virus Infectious Disease-2019 (COVID-19) outbreak originated recently at Wuhan, China in December 2019. It has already spread rapidly to more than 200 countries and has been declared a pandemic by WHO. It is caused by a beta-coronavirus named as SARS-CoV-2. There is no definitive cure, either drug or vaccine, to treat or prevent this viral disease. Recently, the crystal structure of the main protease Mpro has been determined. Mpro is responsible for the proteolytic maturation of the polyprotein essential for the viral replication and transcription, which makes it an important drug target. The discovery of new drug molecules may take years before getting to the clinics. So, considering urgency we performed molecular docking studies using FDA approved drugs to identify molecules that could potentially bind to the substrate-binding site and inhibit SARS-CoV-2 main protease (Mpro). We used the Glide module in Schrodinger software suite to perform molecular docking studies followed by MM-GBSA based energy calculations to score the hit molecules. Molecular docking and manual analysis suggest that several drugs may bind and potentially inhibit Mpro. We also performed molecular simulations studies for selected compounds to evaluate protein-drug interactions. Interestingly, we observed only one antiviral compound, Adefovir, in the top50 list of compounds. Considering bioavailability, lesser toxicity, route of administration some of the top-ranked drugs including lumefantrine (antimalarial), dipyridamole (coronary vasodilator), dihydroergotamine (used for treating migraine), hexoprenaline (anti- asthmatic), riboflavin (vitamin B2) and pantethine (vitamin B5) may be taken forward for further in vitro and in vivo experiments to investigate their therapeutic potential.

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Molecular Docking Study of COVID-19 Main Protease with Clinically Approved Drugs

10.26434/chemrxiv.12318689.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

TACHOUA Wafa ◽

KABRINE Mohamed

Keyword(s):

Docking Study ◽

Docking Studies ◽

Binding Modes ◽

Molecular Docking Study ◽

In Vivo Evaluation ◽

Binding Cavity ◽

Approved Drugs ◽

Potential Inhibitors

A novel strain of coronavirus, namely, Corona Virus Infection Disease 19 has been identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor we performed docking studies on the main virus protease with eight drugs belonging to four pharmacological classes: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. These two compounds revealed a minimum binding energy of -8.87 and -8.71 Kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Lymecycline and Mizolastine interact with specific residues in substrate binding cavity. Thus, Lymecycline and Mizolastione may serve as a tool to fight COVID-19 disease. However, this data need further in vitro and in vivo evaluation to repurpose these two drugs against COVID-19 disease.

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