scholarly journals Search for Novel Lead Inhibitors of Yeast Cytochrome bc1, from Drugbank and COCONUT

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4323
Author(s):  
Ozren Jović ◽  
Tomislav Šmuc
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Ester Group ◽  
Cytochrome Bc1 ◽  
Cytochrome Bc1 Complex ◽  
Lead Compounds ◽  
Almost All ◽  
3D Descriptors

In this work we introduce a novel filtering and molecular modeling pipeline based on a fingerprint and descriptor similarity procedure, coupled with molecular docking and molecular dynamics (MD), to select potential novel quoinone outside inhibitors (QoI) of cytochrome bc1 with the aim of determining the same or different chromophores to usual. The study was carried out using the yeast cytochrome bc1 complex with its docked ligand (stigmatellin), using all the fungicides from FRAC code C3 mode of action, 8617 Drugbank compounds and 401624 COCONUT compounds. The introduced drug repurposing pipeline consists of compound similarity with C3 fungicides and molecular docking (MD) simulations with final QM/MM binding energy determination, while aiming for potential novel chromophores and perserving at least an amide (R1HN(C=O)R2) or ester functional group of almost all up to date C3 fungicides. 3D descriptors used for a similarity test were based on the 280 most stable Padel descriptors. Hit compounds that passed fingerprint and 3D descriptor similarity condition and had either an amide or an ester group were submitted to docking where they further had to satisfy both Chemscore fitness and specific conformation constraints. This rigorous selection resulted in a very limited number of candidates that were forwarded to MD simulations and QM/MM binding affinity estimations by the ORCA DFT program. In this final step, stringent criteria based on (a) sufficiently high frequency of H-bonds; (b) high interaction energy between protein and ligand through the whole MD trajectory; and (c) high enough QM/MM binding energy scores were applied to further filter candidate inhibitors. This elaborate search pipeline led finaly to four Drugbank synthetic lead compounds (DrugBank) and seven natural (COCONUT database) lead compounds—tentative new inhibitors of cytochrome bc1. These eleven lead compounds were additionally validated through a comparison of MM/PBSA free binding energy for new leads against those obtatined for 19 QoIs.

scholarly journals Antiviral potential of phytoligands against chymotrypsin-like protease of COVID‐19 virus using molecular docking studies: An optimistic approach

2020 ◽  
Author(s):  
Ratish Chandra Mishra ◽  
Rosy Kumari ◽  
Shivani Yadav ◽  
Jaya Parkash Yadav
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Drug Repositioning ◽  
Docking Studies ◽  
The Novel ◽  
Lead Compounds ◽  
Recent Outbreak ◽  
Novel Coronavirus ◽  
The City ◽  
Ucsf Chimera

Abstract A recent outbreak of the novel coronavirus, COVID‐19, in the city of Wuhan, Hubei province, China and its ensuing worldwide spread have resulted in lakhs of infections and thousands of deaths. As of now, there are no registered therapies for treating the contagious COVID‐19 infections, henceforth drug repositioning may provide a fast way out. In the present study, a total of thirty-five compounds including commonly used anti-viral drugs were screened against chymotrypsin-like protease (3CLpro) using SwissDock. Interaction between amino acid of targeted protein and ligands was visualized by UCSF Chimera. Docking studies revealed that the phytochemicals such as cordifolin, anisofolin A, apigenin 7-glucoside, luteolin, laballenic acid, quercetin, luteolin-4-glucoside exhibited significant binding energy with the enzyme viz. - 8.77, -8.72, -8.36, -8.35, -8.13, -8.04 and -7.87 Kcal/Mol respectively. Therefore, new lead compounds can be used for drug development against SARS‐CoV‐2 infections.

scholarly journals Molecular Docking Reveals the Potential of Aliskiren, Dipyridamole, Mopidamol, Rosuvastatin, Rolitetracycline and Metamizole to Inhibit COVID-19 Virus Main Protease

2020 ◽  
Author(s):  
Omar Aly
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Drug Repurposing ◽  
Binding Mode ◽  
Type I ◽  
Catalytic Center ◽  
Protease Enzyme ◽  
Main Protease ◽  
Renin Inhibition ◽  
Better Than

<p>Drug repurposing is a fast way to rapidly discover a drug for clinical use. In such circumstances of the spreading of the highly contagious COVID-19, searching for already known drugs is a worldwide demand. In this study, many drugs were evaluated by molecular docking. Among the test compounds, aliskiren (the best), dipyridamole, mopidamol and rosuvastatin showed higher energies of binding than that of the co-crystallized ligand N3 with COVID-19 main protease M<sup>pro</sup>. Rolitetracycline showed the best binding with the catalytic center of the protease enzyme through binding with CYS 145 and HIS 41. Metamizole showed about 86 % of the binding energy of the ligand N3 while the protease inhibitor darunavir showed little bit lower binding energy than N3. These results are promising for using these drugs in the treatment and management of the spreading of COVID-19 virus. Also, it could stimulate clinical trials for the use of these drugs by systemic or <b>inhalation</b> route.</p><p></p><p>The results stimulate the evaluation of these drugs as anti COVID-19 especially aliskiren which showed the highest score of binding with the binding site of N3. This will be added to its renin inhibition and advantage of renin inhibition and possibility of the reduced expression of ACE2[12]. Dipyridamole and mopidamol showed a potential to be more M<sup>pro </sup>inhibitor than ligand N3 and darunavir. Also, dipyridamole has the property of antiviral activity beside its use to decrease the hypercoagulabilty that happens due to COVID infection in addition to the property of promoting type I interferon (IFN) responses and protect mice from viral pneumonia [30]. Rolitetracycling is an amazing in its binding mode in the active site of the protease pocket it seemed as it is tailored to be buried in that pocket. Mopidamol and rosuvastatin are slightly better than the co-crystallized ligand N3 and darunavir in binding mode which nominate the as COVID-19 protease inhibitors. Hopefully this study will help in the repurposing a drug for the treatment of COVID-19.</p><p></p>

scholarly journals Molecular Docking Reveals the Potential of Aliskiren, Dipyridamole, Mopidamol, Rosuvastatin, Rolitetracycline and Metamizole to Inhibit COVID-19 Virus Main Protease

2020 ◽  
Author(s):  
Omar Aly
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Drug Repurposing ◽  
Binding Mode ◽  
Type I ◽  
Catalytic Center ◽  
Protease Enzyme ◽  
Main Protease ◽  
Renin Inhibition ◽  
Better Than

<p>Drug repurposing is a fast way to rapidly discover a drug for clinical use. In such circumstances of the spreading of the highly contagious COVID-19, searching for already known drugs is a worldwide demand. In this study, many drugs were evaluated by molecular docking. Among the test compounds, aliskiren (the best), dipyridamole, mopidamol and rosuvastatin showed higher energies of binding than that of the co-crystallized ligand N3 with COVID-19 main protease M<sup>pro</sup>. Rolitetracycline showed the best binding with the catalytic center of the protease enzyme through binding with CYS 145 and HIS 41. Metamizole showed about 86 % of the binding energy of the ligand N3 while the protease inhibitor darunavir showed little bit lower binding energy than N3. These results are promising for using these drugs in the treatment and management of the spreading of COVID-19 virus. Also, it could stimulate clinical trials for the use of these drugs by systemic or <b>inhalation</b> route.</p><p></p><p>The results stimulate the evaluation of these drugs as anti COVID-19 especially aliskiren which showed the highest score of binding with the binding site of N3. This will be added to its renin inhibition and advantage of renin inhibition and possibility of the reduced expression of ACE2[12]. Dipyridamole and mopidamol showed a potential to be more M<sup>pro </sup>inhibitor than ligand N3 and darunavir. Also, dipyridamole has the property of antiviral activity beside its use to decrease the hypercoagulabilty that happens due to COVID infection in addition to the property of promoting type I interferon (IFN) responses and protect mice from viral pneumonia [30]. Rolitetracycling is an amazing in its binding mode in the active site of the protease pocket it seemed as it is tailored to be buried in that pocket. Mopidamol and rosuvastatin are slightly better than the co-crystallized ligand N3 and darunavir in binding mode which nominate the as COVID-19 protease inhibitors. Hopefully this study will help in the repurposing a drug for the treatment of COVID-19.</p><p></p>

scholarly journals MOLECULAR DOCKING AND MOLECULAR DYNAMICS STUDIES OF ACALYPHA INDICA L. PHYTOCHEMICAL CONSTITUENTS WITH CASPASE-3

2021 ◽  
pp. 210-215
Author(s):  
ELLIN FEBRINA ◽  
RYAN KHUNAM ALAMHARI ◽  
RIZKY ABDULAH ◽  
KERI LESTARI ◽  
JUTTI LEVITA ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Interactions ◽  
Caspase 3 ◽  
Md Simulations ◽  
Binding Mode ◽  
Lead Compounds ◽  
Phytochemical Constituents ◽  
Acalypha Indica ◽  
Native Ligand

Objective: This study investigated the structure-based molecular interactions between phytochemical constituents of Acalypha indica L. and caspase-3. Methods: Thirty-three phytochemical constituents of A. indica were screened against caspase-3. The X-ray crystal structure of human caspase-3 was retrieved from https://www.rcsb.org/structure/. The molecular interactions of the phytochemicals were studied using the AutoDock 4.2 software and followed by molecular dynamics (MD) simulations using the Amber18 software. Results: From this study, 25 screened phytochemicals were found to have a better binding mode than the native ligand. Moreover, the binding stability of the top four hits evaluated by MD indicated that the hydrogen bonds in MD were quite different from the molecular docking results due to the massive receptor and ligand movement in the MD simulations. However, with the exception of stigmasterol, all ligands were able to stabilize the protein. Conclusion: This study suggested that γ-sitosterol acetate, β-sitosterol acetate, and γ-sitosterol might be able to induce caspase-3, thereby activating apoptosis. These high-affinity compounds can bind to caspase-3 more efficiently and were able to stabilize the protein. Therefore, they have the potential to be used as lead compounds in the treatment of cancer.

scholarly journals Molecular Docking Study of drug molecules from Drug Bank database against COVID-19 Mpro protein

2020 ◽  
Author(s):  
Tushar Joshi ◽  
Shalini Mathpal ◽  
Priyanka Sharma ◽  
Tanuja Joshi ◽  
Hemlata Pundir ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Drug Repurposing ◽  
Economic Loss ◽  
Docking Study ◽  
New Drugs ◽  
High Morbidity ◽  
Molecular Docking Study ◽  
Drug Molecules ◽  
Therapeutic Development

Aims: SARS-CoV-2 which is NovelCoronavirushas been disseminated all over the world and causing Coronavirus disease (COVID-19) resulting in many deaths as well as economic loss in several countries.This virus is showinga considerable amount of high morbidity and mortality.Currently, no drugs are available againstSARS-CoV-2. Therefore,for the treatment of disease, researchers are looking fornew drugs that can treat the disease and prevent it to be spread.In this regard,drug repurposingmay help scientists for treating and preventing infections associated with SARS-CoV-2. Drug repurposingis a strategy that can identify new targets for existing drugs that are already approved for the treatment of a disease.Main methods: In this study, we present a virtual screening procedure employing deep lerning regression method in 9101 drugs from Drug bank database against the target Main protease (Mpro) for the treatment of COVID-19. 500 screened compounds were subjected to docking.Key findings: Among those 500 drugs, 10 best drugs were selected, which had better binding energy as compared to the reference molecule. Based on the Binding energy score, we can suggest that the identified drug may be considered for therapeutic development against the virus.Significance: Drug repurposing has many advantages as it could shorten the time and reduce the cost of new drug discovery. This research will help to get new drugs against COVID-19 and help humans against this pandemic disease. Keyword- Drug Repurposing, Deep learning, Molecular Docking, COVID-19, Drug bank database, MPro

scholarly journals In Silico Evaluation of Binding of 2-Deoxy-D-Glucose with Mpro of nCoV to Combat COVID-19

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 135
Author(s):  
Anirudh Pratap Singh Raman ◽  
Kamlesh Kumari ◽  
Pallavi Jain ◽  
Vijay Kumar Vishvakarma ◽  
Ajay Kumar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Binding Energy ◽  
Viral Infection ◽  
Md Simulations ◽  
Analysis Data ◽  
The People ◽  
Novel Coronavirus ◽  
Dynamics Simulations ◽  
Energy Deprivation

COVID-19 has threatened the existence of humanity andthis infection occurs due to SARS-CoV-2 or novel coronavirus, was first reported in Wuhan, China. Therefore, there is a need to find a promising drug to cure the people suffering from the infection. The second wave of this viral infection was shaking the world in the first half of 2021. Drugs Controllers of India has allowed the emergency use of 2-deoxy-D-glucose (2DG) in 2021 for patients suffering from this viral infection. The potentiality of 2-deoxy-D-glucose to intervene in D-glucose metabolism exists and energy deprivation is an effective parameter to inhibit cancer cell development. Once 2DG arrives in the cells, it becomes phosphorylated to 2-deoxy-D-glucose-6-phosphate (2-DG6P), a charged molecule expressively captured inside the cells. On the other hand, 2DG lacks the ability to convert into fructose-6-phosphate, resulting in a hampering of the activity of both glucose-6-phosphate isomerase and hexokinase, and finally causing cell death. Hence, the potential and effectiveness of 2DG with the main protease (Mpro) of novel coronavirus (nCoV) should be investigated using the molecular docking and molecular dynamics (MD) simulations. The ability of 2DG to inhibit the Mpro of nCoV is compared with 2-deoxyglucose (2DAG), an acyclic molecule, and 2-deoxy-D-ribose (2DR). The binding energy of the molecules with the Mpro of nCoV is calculated using molecular docking and superimposed analysis data is obtained. The binding energy of 2DG, 2DR and 2DAG was −2.40, −2.22 and −2.88 kcal/mol respectively. Although the molecular docking does not provide reliable information, therefore, the binding affinity can be confirmed by molecular dynamics simulations. Various trajectories such as Rg, RMSD, RMSF, and hydrogen bonds are obtained from the molecular dynamics (MD) simulations. 2DG was found to be a better inhibitor than the 2DAG and 2DR based on the results obtained from the MD simulations at 300 K. Furthermore, temperature-dependent MD simulations of the Mpro of nCoV with promising 2DG was performed at 295, 310 and 315 K, and the effective binding with the Mpro of nCoV occurred at 295 K. With the use of DFT calculations, optimized geometry and localization of electron density of the frontier molecular orbitals were calculated.

scholarly journals Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2

2020 ◽  
Author(s):  
Vaishali Chandel ◽  
Prem Prakash Sharma ◽  
Sibin Raj ◽  
Brijesh Rathi ◽  
Dhruv Kumar
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Binding Energy ◽  
Active Site ◽  
Hydrophobic Interactions ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Structural Protein ◽  
Maximum Stability ◽  
Spike Proteins

<p>Due to unavailability of therapeutic approach for the novel coronavirus disease (COVID-19), the drug repurposing approach would be the fastest and efficient way of drug development against this deadly disease. We have applied bioinformatics approach for structure-based drug repurposing to identify the potential inhibitors through drug screening, molecular docking and molecular dynamics against non-structural protein 9 (Nsp9) replicase and spike proteins of the SARS-CoV-2 from the FDA approved drugs. We have performed virtual screening of 2000 FDA approved compounds including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis and active phytochemicals against Nsp9 replicase and spike proteins of SARS-CoV-2. Molecular docking was performed using Autodock-Vina. Selected hit compounds were identified based on their highest binding energy and favourable ADME profile. Notably, Conivaptan, an arginine vasopressin antagonist drug exhibited highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present on the active site of Nsp9 replicase. Additionally, Tegobuvir, a non-nucleoside inhibitor of hepatitis C virus exhibited maximum stability with highest binding energy (-8.1 Kcal/mol) on the active site of spike protein. Molecular docking scores were further validated with the molecular dynamics using Schrodinger, which supported strong stability of ligands with proteins at their active site through water bridges, hydrophobic interactions, H-bond. Overall, our findings highlight the fact that Conivaptan and Tegobuvir could be used to control the infection and propagation of SARS-CoV-2 targeting Nsp9 replicase and spike protein, respectively. Moreover, <i>in vitro</i> and <i>in vivo</i> validation of these findings will be helpful in bringing these molecules at the clinical settings.</p>

scholarly journals Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2

2020 ◽  
Author(s):  
Vaishali Chandel ◽  
Prem Prakash Sharma ◽  
Sibin Raj ◽  
Brijesh Rathi ◽  
Dhruv Kumar
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Binding Energy ◽  
Active Site ◽  
Hydrophobic Interactions ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Structural Protein ◽  
Maximum Stability ◽  
Spike Proteins

<p>Due to unavailability of therapeutic approach for the novel coronavirus disease (COVID-19), the drug repurposing approach would be the fastest and efficient way of drug development against this deadly disease. We have applied bioinformatics approach for structure-based drug repurposing to identify the potential inhibitors through drug screening, molecular docking and molecular dynamics against non-structural protein 9 (Nsp9) replicase and spike proteins of the SARS-CoV-2 from the FDA approved drugs. We have performed virtual screening of 2000 FDA approved compounds including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis and active phytochemicals against Nsp9 replicase and spike proteins of SARS-CoV-2. Molecular docking was performed using Autodock-Vina. Selected hit compounds were identified based on their highest binding energy and favourable ADME profile. Notably, Conivaptan, an arginine vasopressin antagonist drug exhibited highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present on the active site of Nsp9 replicase. Additionally, Tegobuvir, a non-nucleoside inhibitor of hepatitis C virus exhibited maximum stability with highest binding energy (-8.1 Kcal/mol) on the active site of spike protein. Molecular docking scores were further validated with the molecular dynamics using Schrodinger, which supported strong stability of ligands with proteins at their active site through water bridges, hydrophobic interactions, H-bond. Overall, our findings highlight the fact that Conivaptan and Tegobuvir could be used to control the infection and propagation of SARS-CoV-2 targeting Nsp9 replicase and spike protein, respectively. Moreover, <i>in vitro</i> and <i>in vivo</i> validation of these findings will be helpful in bringing these molecules at the clinical settings.</p>

scholarly journals A Computational Study to Identify Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro) from Eucalyptus Active Compounds

Computation ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 79
Author(s):  
Ibrahim Ahmad Muhammad ◽  
Kanikar Muangchoo ◽  
Auwal Muhammad ◽  
Ya’u Sabo Ajingi ◽  
Ibrahim Yahaya Muhammad ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Computational Study ◽  
Md Simulations ◽  
Binding Energies ◽  
Drug Candidate ◽  
Global Public Health ◽  
Main Protease ◽  
Poisson Boltzmann ◽  
Potential Inhibitors

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found to be a severe threat to global public health in late 2019. Nevertheless, no approved medicines have been found to inhibit the virus effectively. Anti-malarial and antiviral medicines have been reported to target the SARS-CoV-2 virus. This paper chose eight natural eucalyptus compounds to study their binding interactions with the SARS-CoV-2 main protease (Mpro) to assess their potential for becoming herbal drugs for the new SARS-CoV-2 infection virus. In-silico methods such as molecular docking, molecular dynamics (MD) simulations, and Molecular Mechanics Poisson Boltzmann Surface Area (MM/PBSA) analysis were used to examine interactions at the atomistic level. The results of molecular docking indicate that Mpro has good binding energy for all compounds studied. Three docked compounds, α-gurjunene, aromadendrene, and allo-aromadendrene, with highest binding energies of −7.34 kcal/mol (−30.75 kJ/mol), −7.23 kcal/mol (−30.25 kJ/mol), and −7.17 kcal/mol (−29.99 kJ/mol) respectively, were simulated with GROningen MAchine for Chemical Simulations (GROMACS) to measure the molecular interactions between Mpro and inhibitors in detail. Our MD simulation results show that α-gurjunene has the strongest binding energy of −20.37 kcal/mol (−85.21 kJ/mol), followed by aromadendrene with −18.99 kcal/mol (−79.45 kJ/mol), and finally allo-aromadendrene with −17.91 kcal/mol (−74.95 kJ/mol). The findings indicate that eucalyptus may be used to inhibit the Mpro enzyme as a drug candidate. This is the first computational analysis that gives an insight into the potential role of structural flexibility during interactions with eucalyptus compounds. It also sheds light on the structural design of new herbal medicinal products against Mpro.

scholarly journals DRDOCK: A drug repurposing platform integrating automated docking, simulations and a log-odds-based drug ranking scheme

2021 ◽  
Author(s):  
Kun-Lin Tsai ◽  
Lee-Wei Yang
Keyword(s):  
Molecular Docking ◽  
Molecular Dynamic ◽  
Drug Screening ◽  
Disease Outbreaks ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Structure Based Drug Design ◽  
Docking Simulations ◽  
Ranking Scheme ◽  
Log Odds

AbstractMotivationDrug repurposing, where drugs originally approved to treat a disease are reused to treat other diseases, has received escalating attention especially in pandemic years. Structure-based drug design, integrating small molecular docking, molecular dynamic (MD) simulations and AI, has demonstrated its evidenced importance in streamlining new drug development as well as drug repurposing. To perform a sophisticated and fully automated drug screening using all the FDA drugs, intricate programming, accurate drug ranking methods and friendly user interface are very much needed.ResultsHere we introduce a new web server, DRDOCK, Drug Repurposing DOcking with Conformation-sampling and pose re-ranKing - refined by MD and statistical models, which integrates small molecular docking and molecular dynamic (MD) simulations for automatic drug screening of 2016 FDA-approved drugs over a user-submitted single-chained target protein. The drugs are ranked by a novel drug-ranking scheme using log-odds (LOD) scores, derived from feature distributions of true binders and decoys. Users can submit a selection of LOD-ranked poses for further MD-based binding affinity evaluation. We demonstrated that our platform can indeed recover one of the substrates for nsp16, a cap ribose 2’-O methyltransferase, and recommends XXX, could be repurposed for the COVID19 treatment. All the sampled docking poses and trajectories can be 3D-viewed and played via our web interface. This platform shall be easy-to-use for general scientists and medicinal researchers to carry out drug repurposing within a couple of days which should add value to our timely responses to, particularly, emergent disease outbreaks.Availability and implementationDRDOCK can be freely accessed from https://dyn.life.nthu.edu.tw/drdock/. (Due to the hardware upgrade, the service is NOT available before 2/15, 2021)

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