Repurposing of FDA-approved Drugs against Active Site and Potential Allosteric Drug Binding Sites of COVID-19 Main Protease

Mapping Intimacies ◽

10.22541/au.161841491.18932381/v1 ◽

2021 ◽

Author(s):

Merve Yuce ◽

Erdem Cicek ◽

Tuğçe İnan ◽

Aslıhan Başak Dağ ◽

Özge Kürkçüoğlu ◽

...

Keyword(s):

Active Site ◽

Social Life ◽

Binding Free Energy ◽

Antiviral Drug ◽

Drug Binding ◽

Allosteric Site ◽

Main Protease ◽

Allosteric Sites ◽

Approved Drugs ◽

Fda Approved Drugs

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, FDA-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. 14 best molecule hits for the active site of Mpro are determined. 6 of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and -42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infection

Repurposing of FDA ‐approved Drugs against Active Site and Potential Allosteric Drug Binding Sites of COVID ‐19 Main Protease

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.26164 ◽

2021 ◽

Author(s):

Merve Yuce ◽

Erdem Cicek ◽

Tugce Inan ◽

Aslihan Basak Dag ◽

Ozge Kurkcuoglu ◽

...

Keyword(s):

Active Site ◽

Binding Sites ◽

Drug Binding ◽

Main Protease ◽

Drug Binding Sites ◽

Approved Drugs ◽

Fda Approved Drugs

Repurposing of FDA approved drugs targeting Main protease MPro for SARS-CoV-2

10.21203/rs.3.rs-72576/v1 ◽

2020 ◽

Author(s):

Suryakant Tiwari ◽

Raghav Jain ◽

Indrani Banerjee

Keyword(s):

Drug Discovery ◽

Virtual Screening ◽

Active Site ◽

Ligand Docking ◽

Kcal Mole ◽

Main Protease ◽

Alternative Approach ◽

Repurposed Drugs ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract SARS-CoV-2 is one of the greatest pandemics in the history. There is no medicine or vaccine yet discovered to control the outbreak. The paper deals with repurposing existing drugs to control the outbreak of SARS-CoV-2 virus.Ten FDA-approved drugs namely Indinavir, Nelfinavir, Letermovir, Irinotecan, Elbasvir, Saquinavir, Darunavir, Raltegravir, Atazanavir and Amprenavir were studied. In silico methods for virtual screening of protein-ligand docking of these drugs against SARS-CoV-2 MPro was performed. The binding efficiency of the drugs against viral main protease MPro was significantly high to inhibit SARS-CoV-2.The results confirmed that Atazanavir, Nelfinavir, and Letermovir not only occupied the active site of Mpro but also showed increased binding affinity (-10.36 kcal/mole, -9.47 kcal/mole and -9.43 kcal/mole) even more than of control drugs of Lopinavir (-8.71 kcal/mole) and Ritonavir (-8.08 kcal/mole). These repurposed drugs can be used in combination or individually as an alternative approach for rapid drug discovery against SARS-CoV-2

Crystal-Structures-Guided Design of Fragment-Based Drugs for Inhibiting the Main Protease of SARS-CoV-2

10.21203/rs.3.rs-80869/v1 ◽

2020 ◽

Author(s):

Binquan Luan ◽

Tien Huynh

Keyword(s):

Binding Free Energy ◽

Dynamics Simulation ◽

Drug Molecule ◽

Protein Targets ◽

Main Protease ◽

Potent Drug ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Efficacious Drug ◽

Better Than

Abstract Since the beginning of the COVID-19 pandemic, researchers and scientists across the globe are racing to find a cure for the highly contagious infectious disease caused by the SARS-CoV-2 virus. Despite many promising ongoing progress, there are currently no FDA approved drugs to treat infected patients. Among the various protein targets of SARS-CoV-2 virus, the main protease (Mpro) has attracted most interests. Recently, the crowdsourcing of drug discovery for inhibiting Mpro have yielded a plenty of drug fragments resolved inside the active site of Mpro via the crystallography method. Following the principle of fragment-based drug design (FBDD), we are motivated to design a potent drug molecule through merging several of these newly discovered drug fragments. Among various designed ligands, we found that B19 by merging three fragments JFM, U0P and HWH is the most stable one, evidenced through extensive (~10 μs totally) all-atom molecular dynamics simulation. We further estimated that the binding free energy of B19 is comparable or even a little better than that of a native protein ligand processed by Mpro. Our promising results suggest that B19 can potentially be an efficacious drug molecule for inhibiting Mpro of SARS-CoV-2.

Interactions mechanism of commonly used drugs for the treatment of Covid-19

Bulletin of the Chemical Society of Ethiopia ◽

10.4314/bcse.v34i3.16 ◽

2021 ◽

Vol 34 (3) ◽

pp. 613-623

Author(s):

S. Celik ◽

A. D. Demirag ◽

A. E. Ozel ◽

S. Akyuz

Keyword(s):

Binding Free Energy ◽

Autodock Vina ◽

Spike Glycoprotein ◽

Docking Analysis ◽

Drug Molecules ◽

Protease Enzyme ◽

Main Protease ◽

Poisson Boltzmann ◽

Approved Drugs ◽

Fda Approved Drugs

In this study conformation analysis of seven drugs commonly used in the treatment of COVID-19 was performed. The most stable conformers of the drug molecules were used as initial data for docking analysis. Using the Cavityplus program, the probable most active binding sites of both apo and holo forms of COVID-19 main protease enzyme (Mpro) and spike glycoprotein of SARSCoV-2 receptors were determined. The interaction mechanisms of the 7 FDA approved drugs (arbidol, colchicine, dexamethasone, favipiravir, galidesivir, hydroxychloroquine, remdesivir) were examined using the AutoDock Vina program. The six of the seven drugs were found to be more stable in binding to apo form of COVID-19 Mpro and spike glycoprotein. Moreover, a set of molecular mechanics (MM) Poisson-Boltzmann (PB) surface area (SA) calculations on the investigated drugs-protein systems were performed and the estimated binding free energy of remdesivir and the apo form of Mpro system was found to be the best. The interaction results of FDA drugs with the apo form of COVID-19 Mpro and spike glycoprotein can play an important role for the treatment of COVID-19. KEY WORDS: COVID-19, Drugs, Molecular modelling, Conformational analysis, Molecular docking Bull. Chem. Soc. Ethiop. 2020, 34(3), 613-623. DOI: https://dx.doi.org/10.4314/bcse.v34i3.16

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.

A screen of FDA-approved drugs identifies inhibitors of protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3)

Scientific Reports ◽

10.1038/s41598-021-89668-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Dylan R. Rivas ◽

Mark Vincent C. Dela Cerna ◽

Caroline N. Smith ◽

Shilpa Sampathi ◽

Blaine G. Patty ◽

...

Keyword(s):

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Dependent Manner ◽

Allosteric Site ◽

Human Embryonic Kidney Cells ◽

Protein Tyrosine ◽

Tumor Cell Migration ◽

Colorectal Cancer Cells ◽

Approved Drugs ◽

Fda Approved Drugs

AbstractProtein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells with no impact on cell viability. Both drugs prevented migration of human colorectal cancer cells in a PRL-3 dependent manner and were selective towards PRLs over other phosphatases. In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CX5R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.

Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations

Processes ◽

10.3390/pr9061004 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1004

Author(s):

Mahmoud A. El Hassab ◽

Mohamed Fares ◽

Mohammed K. Abdel-Hamid Amin ◽

Sara T. Al-Rashood ◽

Amal Alharbi ◽

...

Keyword(s):

Drug Design ◽

Active Site ◽

Binding Free Energy ◽

Stable Complex ◽

Active Site Residues ◽

Structure Based Drug Design ◽

Enzyme Active Site ◽

Potential Inhibitor ◽

Main Protease ◽

Covalent Docking

Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.

Potential Binding Efficiency of Antiviral Drug Lopinavir Targeted to the Catalytic Dyad, His41 - Cys145 of SARS CoV -2 Main Protease

10.26434/chemrxiv.12453644.v1 ◽

2020 ◽

Author(s):

Muthu Raj S ◽

Manohar M ◽

Mohan M ◽

Ganesh P ◽

Marimuthu K

Keyword(s):

Antiviral Drug ◽

Emergency Situation ◽

Viral Disease ◽

New Drugs ◽

Viral Population ◽

Protease Inhibition ◽

Main Protease ◽

Model Drug ◽

Approved Drugs ◽

Catalytic Dyad

<p>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.</p>

Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

10.1101/356956 ◽

2018 ◽

Author(s):

R. N. V. Krishna Deepak ◽

Ahmad Abdullah ◽

Priti Talwar ◽

Hao Fan ◽

Palaniyandi Ravanan

Keyword(s):

Active Site ◽

Caspase 3 ◽

Specific Activity ◽

Special Importance ◽

Allosteric Inhibitors ◽

Dimerization Interface ◽

Executioner Caspases ◽

Approved Drugs ◽

Fda Approved Drugs

AbstractThe regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed five compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that four out of the five drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 μM. Structural analysis of the docking poses show the four compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of four novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.

Screening of FDA Approved Drugs Against COVID-19 Main Protease: Coronavirus Disease

10.20944/preprints202004.0062.v1 ◽

2020 ◽

Cited By ~ 4

Author(s):

Vijayakumar Balakrishnan ◽

Karthik Lakshminarayanan

Keyword(s):

Vaccine Development ◽

New Drugs ◽

World Health ◽

Wuhan City ◽

Drug Candidates ◽

Human Contact ◽

Main Protease ◽

Potent Drug ◽

Approved Drugs ◽

Fda Approved Drugs

In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger’s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.