Molecular docking and dynamics simulation of FDA approved drugs with the main protease from 2019 novel coronavirus

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.

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Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

Communications Biology ◽

10.1038/s42003-020-01577-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Vicky Mody ◽

Joanna Ho ◽

Savannah Wills ◽

Ahmed Mawri ◽

Latasha Lawson ◽

...

Keyword(s):

Inhibitory Effect ◽

Dynamics Simulation ◽

Simulation Studies ◽

Inhibitory Effects ◽

Major Threat ◽

Main Protease ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

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Investigation of Cu metal nanoparticles with different morphologies to inhibit SARS-CoV-2 main protease and spike glycoprotein using Molecular Docking and Dynamics Simulation

Journal of Molecular Structure ◽

10.1016/j.molstruc.2021.132301 ◽

2021 ◽

pp. 132301

Author(s):

Mohammadreza Aallaei ◽

Elaheh Molaakbari ◽

Paridokht Mostafavi ◽

Navvabeh Salarizadeh ◽

Rahime Eshaghi Maleksah ◽

...

Keyword(s):

Molecular Docking ◽

Metal Nanoparticles ◽

Dynamics Simulation ◽

Spike Glycoprotein ◽

Main Protease ◽

Molecular Docking And Dynamics

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Repurposing of FDA Approved Drugs for the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

10.26434/chemrxiv.12278066 ◽

2020 ◽

Author(s):

Abhik Kumar Ray ◽

Parth Sarthi Sen Gupta ◽

Saroj Kumar Panda ◽

Satyaranjan Biswal ◽

Malay Kumar Rana

Keyword(s):

Virtual Screening ◽

Binding Energies ◽

Great Promise ◽

Main Protease ◽

Promising Target ◽

Inhibitory Potential ◽

Novel Coronavirus ◽

Approved Drugs ◽

Potential Inhibitors ◽

Fda Approved Drugs

COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal/mol), out of which the top two drugs Velpatasvir (-9.1 kcal/mol) and Glecaprevir (-9.0 kcal/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor α-ketoamide 13B (-6.7 kcal/mol) or Indinavir (-7.5 kcal/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The in-silico efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway.

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Evaluation of Yashtimadhu (Glycyrrhiza glabra) active Phytochemicals Against Novel Coronavirus (SARS-CoV-2)

10.21203/rs.3.rs-26480/v1 ◽

2020 ◽

Author(s):

Dharmendra Kumar Maurya

Keyword(s):

Viral Entry ◽

Virus Disease ◽

Scientific Basis ◽

Docking Studies ◽

Angiotensin Converting Enzyme 2 ◽

Main Protease ◽

Docking Approach ◽

Novel Coronavirus ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract Corona Virus Disease 2019 (COVID-19) caused by a novel coronavirus emerged from Wuhan, China in December 2019. It has spread to more than 205 countries and become pandemic now. Currently, there are no FDA approved drugs or vaccines available and hence several studies are going on in search of suitable drug that can target viral proteins or host receptor for the prevention and management of COVID-19. The search for plant-based anti-viral agents against the SARS-CoV-2 is promising because several of plants have been shown to possess anti-viral activities against different viruses. Here, we used molecular docking approach to explore the use of Indian Ayurvedic herbs, Yashtimadhu in prevention and management of COVID-19. In the present study we have evaluated the effectiveness of phytochemicals found in Yashtimadhu against Main Protease (Mpro), Spike (S) protein and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor and furin protease. Apart from this, we have also performed in-silico drug-likeness and predicted pharmacokinetics of the selected phytochemicals found in the Yashtimadhu. Our study shows that several phytochemicals found in this plant have potential to bind with important proteins of SARS-CoV-2 which are essential for viral infection and replication. Overall our study provides scientific basis in terms of binding of active ingredients present in Yashtimadhu with SARS-CoV-2 target proteins. Our docking studies reveal that Yashtimadhu may inhibit the viral severity by interfering with viral entry as well as its multiplication in the infected persons. Thus Yashtimadhu may be helpful in the prevention and management of the COVID-19.

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Molecular Docking and Dynamics Simulation Study of Hyrtios erectus Isolated Scalarane Sesterterpenes as Potential SARS-CoV-2 Dual Target Inhibitors

Biology ◽

10.3390/biology10050389 ◽

2021 ◽

Vol 10 (5) ◽

pp. 389

Author(s):

Sameh S. Elhady ◽

Reda F. A. Abdelhameed ◽

Rania T. Malatani ◽

Abdulrahman M. Alahdal ◽

Hanin A. Bogari ◽

...

Keyword(s):

Molecular Docking ◽

Md Simulation ◽

Protein Complexes ◽

Antiviral Agents ◽

Binding Energies ◽

Dynamics Simulation ◽

Main Protease ◽

Simulation Parameters ◽

Molecular Docking And Dynamics ◽

Dual Target

Presently, the world is under the toll of pandemic coronavirus disease-2019 (COVID-19) outbreak caused by SARS-CoV-2. Lack of effective and safe therapeutics has stressed the scientific community for developing novel therapeutics capable of alleviating and stopping this pandemic. Within the presented study, molecular docking, ADME properties and all-atom molecular dynamic (MD) simulation, along with two standard antiviral agents (lopinavir and benzopurpurin-4B), were applied to investigate 15 scalaranes sesterterpenes natural compounds, purified from the Red Sea marine sponge Hyrtios erectus, as potential COVID-19 dual-target inhibitors. Following multi-step docking within COVID-19 main protease and Nsp15 endoribonuclease cavities, nine promising drug-like compounds exhibited higher docking scores as well as better interactions with the target’s crucial residues than those of reference ligands. Compounds 2, 6, 11, and 15, were predicted to simultaneously subdue the activity of the two COVID-19 targets. Dynamics behavior of the best-docked molecules, compounds 15 and 6, within COVID-19 target pockets showed substantial stability of ligand-protein complexes as presented via several MD simulation parameters. Furthermore, calculated free-binding energies from MD simulation illustrated significant ligand’s binding affinity towards respective target pockets. All provided findings supported the utility of scalarane-based sesterterpenes, particularly compounds 15 and 6, as promising lead candidates guiding the development of effective therapeutics against SARS-CoV-2.

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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.

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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.

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In Silico Screening of Potent Bioactive Compounds from Honey Bee Products Against COVID-19 Target Enzymes

10.26434/chemrxiv.12644102 ◽

2020 ◽

Author(s):

Moataz A. Shaldam ◽

Galal Yahya ◽

Nashwa H. Mohamed ◽

Mohamed M. Abdel-Daim ◽

Yahya Al Naggar

Keyword(s):

Molecular Docking ◽

Honey Bee ◽

Bioactive Compounds ◽

Viral Infections ◽

Good Alternative ◽

The Novel ◽

Main Protease ◽

Novel Coronavirus ◽

Approved Drugs ◽

Antiviral Medications

From the early days of the COVID-19 pandemic, side by side to immense investigates to design specific drugs or to develop a potential vaccine for the novel coronavirus. Myriads of FDA approved drugs are massively repurposed for COVID-19 treatment based on molecular docking of selected protein targets that play vital for the replication cycle of the virus. Honey bee products are well known of their nutritional values and medicinal effects. Antimicrobial activity of bee products and natural honey have been documented in several clinical studies and was considered a good alternative for antiviral medications to treat some viral infections. Bee products contain bioactive compounds in the form of a collection of phenolic acids, flavonoids and terpenes of natural origin. We revealed by molecular docking the profound binding affinity of 14 selected phenolics and terpenes present in honey and propolis (bees glue) against the main protease (Mpro) and RNA dependent RNA polymerase (RdRp) enzymes of the novel 2019-nCoV coronavirus. Of these compounds, p-coumaric acid, ellagic acid, kaemferol and quercetin has the strongest interaction with the 2019-nCoV target enzymes, and they may be considered as an effective 2019-nCoV inhibitors.

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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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