Repurposing drug molecule against SARS-Cov-2 (COVID-19) through molecular docking and dynamics: a quick approach to pick FDA-approved drugs

Zika virus is a mosquito borne pathogen with a single strand RNA genome. Human infection with this virus is usually asymptomatic, however outbreaks reported in both Pacific region and Latin America have been associated with increase in frequency of microcephaly in newborns and fetuses of infected mothers. Also, the incidence of Guillain-Barré syndrome had also increased among adults with Zika virus infection. Currently, neither vaccine nor antiviral drug has been developed against Zika virus. Structure based virtual screening can be employed, through drug repurposing strategy, to accelerate the identification of potential anti-Zika virus candidates. As such, virtual screening of approved drugs against Zika virus NS2B/NS3 protease can help to recognize new hits capable of hindering viral ability to replicate and evade immune system of the host. In this computational study, we have screened 1615 FDA approved drugs against NS2B/NS3 protease enzyme of Zika virus by using both molecular docking and dynamics simulation. Our virtual screening results indicate that the anti-muscarinic agent Darifenacin and the anti-diarrheal agent Loperamide may have a promising capacity to inhibit Zika virus NS2B/NS3 protease. According to molecular docking and dynamics simulation, these two approved drugs have good binding capacity to NS2B/NS3 as reported by docking energy of binding and MM-PBSA binding energy. In addition, both Darifenacin and Loperamide were able to maintain close proximity to protease crystal throughout simulation period. However, invitro evaluation of these two drugs against Zika virus NS2B/NS3 protease is required to confirm these computational results.

Download Full-text

Mulberrofuran G, a Potent Inhibitor of SPIKE Protein of SARS Corona Virus 2

Journal of Pharmaceutical Care ◽

10.18502/jpc.v9i2.6610 ◽

2021 ◽

Author(s):

Fatemeh Sadat Hosseini ◽

Mohammad Reza Motamedi

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

Active Site ◽

Potential Role ◽

Potent Inhibitor ◽

Screening Method ◽

Spike Protein ◽

Treatment Agent ◽

Approved Drugs ◽

Fda Approved Drugs

Background: At the onset of the 2020 year, Coronavirus disease (COVID-19) has become a pandemic and infected many people worldwide. Despite all efforts, no cure was found for this infection. Bioinformatics and medicinal chemistry have a potential role in the primary consideration of drugs to treat this infection. With virtual screening and molecular docking, some potent compounds and medications can be found and modified and then applied to treat disease in the next steps. Methods: By virtual screening method and PRYX software, some Food and Drug Administration (FDA) approved drugs and natural compounds have been docked with the SPIKE protein of SARS-CoV-2. Some more potent agents have been selected, and then new structures are designed with better affinity than them. After that, we searched for the molecules with a similar structure to designed compounds to find the most potent compound to our target. Results: Because of the study of structures and affinities, mulberrofuran G was the most potent compound in this study. The compound has interacted strongly with residues in the probably active site of SPIKE. Conclusion: Mulberrofuran G can be a treatment agent candidate for COVID-19 because of its good affinity to SPIKE of the virus and inhibition of virus-cell adhesion and entrance.

Download Full-text

In Silico Identification of Active Phytochemicals against COVID-19 by Targeting the SARS-CoV-2 Spike Glycoprotein Through Molecular Docking: A Drug Repurposing Approach

International Journal for Research in Applied Sciences and Biotechnology ◽

10.31033/ijrasb.8.2.10 ◽

2021 ◽

Vol 8 (2) ◽

pp. 72-87

Author(s):

Rathan Kumar

Keyword(s):

Molecular Docking ◽

Antiviral Treatment ◽

Drug Repurposing ◽

Modern Human ◽

Binding Affinities ◽

In Silico Identification ◽

Adme Properties ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Natural Inhibitors

The spread of coronavirus disease (COVID-19) has become one of the most significant pandemics in modern human history, affecting more than 70 million people worldwide. Currently, only a few fda-approved drugs have suggested fighting the infection, in the absence of a specific antiviral treatment. Thus, repurposing the presently available drugs or using plant-based bioactive compounds can be the fastest possible solution. In this study, the computational methodology of molecular docking techniques was performed to screen and identify the viable potent inhibitors against the SARS-CoV-2 spike protein from a library of 200 active phytochemicals, based on their highest binding affinity towards the target protein. Later, the binding affinities of these phytochemicals were compared with that of the fda-approved drug fluvoxamine, which is currently in use against the mild COVID-19 patients. Out of these, 86 phytochemicals that exhibited better binding energy of value ≤-7.00kcal/mol, is selected for adme (absorption, distribution, metabolism, and excretion) analysis and drug likeliness studies to check the feasibility of these compounds. Wherein, 79 out of 86 phytochemicals showed a better theoretical affinity with sufficiently bearable adme properties. Thus, they can be the lead molecule for further investigation and validation processes towards developing natural inhibitors against the SARS-CoV-2 virus.

Download Full-text

Computational studies by molecular docking of some antiviral drugs with COVID-19 receptors are an approach to medication for COVID-19

Open Chemistry ◽

10.1515/chem-2021-0024 ◽

2021 ◽

Vol 19 (1) ◽

pp. 245-264

Author(s):

Magda H. Abdellatiif ◽

Amena Ali ◽

Abuzer Ali ◽

Mostafa A. Hussien

Keyword(s):

Molecular Docking ◽

Antiviral Drug ◽

Chemotherapeutic Agents ◽

The Novel ◽

Drug Molecules ◽

Study Results ◽

Promising Treatment ◽

Novel Coronavirus ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract The COVID-19 outbreak is a matter of concern worldwide due to unavailability of promising treatment comprising medication or vaccination till date. The discovery of antiviral drug is of immense importance in the existing spread of novel coronavirus. The goal of the present study was to evolve an opposite antiviral drug against the novel COVID-19 virus. A directly succeeding perspective would be to use the prevailing influential drugs from several antimicrobial and chemotherapeutic agents. The encouraging approach is to identify promising drug molecules and compounds through virtual screening via molecular docking of FDA-approved drugs and some previously synthesized pyridone and coumarin derivatives for probable therapeutic outcome. In this conceptual milieu, an effort has been made to propose a computational in silico relationship among FDA-approved drugs and coronavirus-associated receptors and proteins. The study results were evaluated on the basis of a dock score by using molecular operating environment. Out of 15 compounds screened, the compounds with the best docking scores toward their targets was 3d. Therefore, compound 3d deserves further investigations and clinical trials as a possible therapeutic inhibitor of the COVID-19 caused by the novel SARS-CoV-2.

Download Full-text

Folate and Tolazamide: Potential competitive inhibitors of barbiturate by in-silico molecular docking

10.1101/2020.06.27.174938 ◽

2020 ◽

Author(s):

Kumar Sharp

Keyword(s):

Molecular Docking ◽

Conformational Changes ◽

In Silico ◽

Low Cost ◽

Effective Management ◽

Competitive Inhibitors ◽

Adults And Children ◽

Approved Drugs ◽

In Silico Molecular Docking ◽

Fda Approved Drugs

AbstractBarbiturates are the first line drugs for treatment of epilepsy for adults and children in the developing world because of its low cost and proven effectiveness. Due to their adverse effects, no effective management of toxicity and difficulty in determining correct dosage, benzodiazepines are preferred over them. It is also used as a recreational drug, thereby contributing to cases of overdose. My present study was to find the inhibitors of barbiturates by in-silico molecular docking. This approach can highlight only competitive inhibitors as molecules in-silico are rigid and do not produce conformational changes in structure by allosteric binding. 450 FDA-approved drugs were docked to active site of barbiturate of Gleobacter ligand-gated ion channel (GLIC). Drug interactions were visualized, literature search was done to bring out the final results. Tolazamide, an oral anti-diabetic drug and 5-methyltetrahydrofolate, active metabolite of folic acid produced desired results. These results should be used clinically for validation.

Download Full-text

Reappraisal of trifluperidol against Nsp3 as a potential therapeutic for novel COVID-19: a molecular docking and dynamics study

Future Virology ◽

10.2217/fvl-2020-0361 ◽

2021 ◽

Author(s):

Ajita Pandey ◽

Mohit Sharma

Keyword(s):

Infectious Disease ◽

Molecular Dynamics ◽

Antiviral Agents ◽

Dynamics Simulation ◽

Regression Methods ◽

Fast Spreading ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Spreading Disease ◽

Molecular Docking And Dynamics

Novel COVID-19 is a highly infectious disease that is caused by the recently discovered SARS-CoV-2. It is a fast-spreading disease that urgently requires therapeutics. The current study employed computational regression methods to target the ADP-ribose phosphatase (ADRP) domain of Nsp3 using FDA-approved drugs. Identified leads were further investigated using molecular dynamics simulation (MDS). The screening and MDS results suggest that trifluperidol could be a novel inhibitor of the ADRP domain of Nsp3. Trifluperidol could, therefore, be used to help control the spread of COVID-19, either alone or in combination with antiviral agents.

Download Full-text

Combined Deep Learning and Molecular Docking Simulations Approach Identifies Potentially Effective FDA Approved Drugs for Repurposing Against SARS-CoV-2

10.26434/chemrxiv.12227363.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Muhammad Umer Anwar ◽

Farjad Adnan ◽

Asma Abro ◽

Muhammad Rayyan Khan ◽

Asad Ur Rehman ◽

...

Keyword(s):

Deep Learning ◽

Molecular Docking ◽

Active Sites ◽

Drug Repurposing ◽

Viral Proteins ◽

Penicillin G ◽

Computational Approaches ◽

Docking Simulations ◽

Approved Drugs ◽

Fda Approved Drugs

The ongoing pandemic of Coronavirus Disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a serious threat to global public health. Currently no approved drug or vaccine exists against SARS-CoV-2. Drug repurposing, represented as an effective drug discovery strategy from existing drugs, is a time efficient approach to find effective drugs against SARS-CoV-2 in this emergency situation. Both experimental and computational approaches are being employed in drug repurposing with computational approaches becoming increasingly popular and efficient. In this study, we present a robust experimental design combining deep learning with molecular docking experiments to identify most promising candidates from the list of FDA approved drugs that can be repurposed to treat COVID-19. We have employed a deep learning based Drug Target Interaction (DTI) model, called DeepDTA, with few improvements to predict drug-protein binding affinities, represented as KIBA scores, for 2,440 FDA approved and 8,168 investigational drugs against 24 SARS-CoV-2 viral proteins. FDA approved drugs with the highest KIBA scores were selected for molecular docking simulations. We ran docking simulations for 168 selected drugs against 285 total predicted and/or experimentally proven active sites of all 24 SARS-CoV-2 viral proteins. We used a recently published open source AutoDock based high throughput screening platform virtualflow to reduce the time required to run around 50,000 docking simulations. A list of 49 most promising FDA approved drugs with best consensus KIBA scores and AutoDock vina binding affinity values against selected SARS-CoV-2 viral proteins is generated. Most importantly, anidulafungin, velpatasvir, glecaprevir, rifabutin, procaine penicillin G, tadalafil, riboflavin 5’-monophosphate, flavin adenine dinucleotide, terlipressin, desmopressin, elbasvir, oxatomide, enasidenib, edoxaban and selinexor demonstrate highest predicted inhibitory potential against key SARS-CoV-2 viral proteins.

Download Full-text

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.

Download Full-text