scholarly journals In silico discovery of SARS-CoV-2 main protease inhibitors from the carboline and quinoline database

2021 ◽  
Author(s):  
Eldar Muhtar ◽  
Mengyang Wang ◽  
Haimei Zhu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanics ◽  
Protease Inhibitors ◽  
Surface Area ◽  
In Silico ◽  
Binding Energies ◽  
Main Protease ◽  
Poisson Boltzmann ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Aim: SARS-CoV-2 caused more than 3.8 million deaths according to the WHO. In this urgent circumstance, we aimed at screening out potential inhibitors targeting the main protease of SARS-CoV-2. Materials & methods: An in-house carboline and quinoline database including carboline, quinoline and their derivatives was established. A virtual screening in carboline and quinoline database, 50 ns molecular dynamics simulations and molecular mechanics Poisson−Boltzmann surface area calculations were carried out. Results: The top 12 molecules were screened out preliminarily. The molecular mechanics Poisson−Boltzmann surface area ranking showed that p59_7m, p12_7e, p59_7k stood out with the lowest binding energies of -24.20, -17.98, -17.67 kcal/mol, respectively. Conclusion: The study provides powerful in silico results that indicate the selected molecules are valuable for further evaluation as SARS-CoV-2 main protease inhibitors.

scholarly journals Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7458
Author(s):  
Amin Osman Elzupir
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Mechanics ◽  
Surface Area ◽  
Active Sites ◽  
Inhibitory Effect ◽  
Binding Energies ◽  
Poisson Boltzmann ◽  
The Stability ◽  
Dynamics Simulations

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics–Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics–generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from −4.6 ± 0.14 to −7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP–3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of −25.53 and −7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.

scholarly journals Using molecular dynamics simulations to evaluate active designs of cephradine hydrolase by molecular mechanics/Poisson–Boltzmann surface area and molecular mechanics/generalized Born surface area methods

RSC Advances ◽  
2019 ◽  
Vol 9 (24) ◽  
pp. 13868-13877 ◽  
Author(s):  
Jing Xue ◽  
Xiaoqiang Huang ◽  
Yushan Zhu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanics ◽  
Surface Area ◽  
Assessment Method ◽  
Dynamics Simulation ◽  
Enzyme Design ◽  
Generalized Born ◽  
Computational Enzyme Design ◽  
Poisson Boltzmann ◽  
Dynamics Simulations

A quantitative assessment method for computational enzyme design was developed to rank the active designs of cephradine hydrolase based on molecular dynamics simulation.

scholarly journals In silico screening of W. salutaris bioactive constituents reveal betulinic acid, ursolic acid acetate and eucosterol as potential M. tuberculosis antagonists targeting FabF

2021 ◽  
Author(s):  
Nokukhanya Gumede ◽  
Kgothatso E. Machaba ◽  
Umar Ndagi ◽  
Hezekiel M. Kumalo ◽  
Ndumiso N. Mhlongo
Keyword(s):  
Ursolic Acid ◽  
Betulinic Acid ◽  
In Silico ◽  
Fatty Acid Biosynthesis ◽  
Binding Energies ◽  
Active Site Residues ◽  
Bioactive Constituents ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Tuberculosis (TB) remains a long-standing burdening disease to control worldwide. The lengthy current TB treatment, which boasts with unbearable adverse effects, and frequent emergence of drug resistant strains of M. tuberculosis lays an increasing burden. This behests urgent discovery and development of alternative novel medicine to alleviate TB. In this report, in silico methods were applied to examine the propensity of W. salutaris active compounds as potential inhibitors of M. tuberculosis fatty acid biosynthesis protein (FabF). Thirteen compounds were virtually screened against FabF and subjected to molecular dynamics simulations and post-dynamics analyses to examine their inhibitory potential. Betulinic acid, ursolic acid and ursolic acid acetate had the best binding energies and hence the best inhibitory potential against FabF and desirable cytotoxicity profile. These compounds bind and interact with FabF active site residues to exert their inhibitory potential. Findings in this preliminary report warrant further experimental validation towards the development of these compounds as potential drugs targeting FabF in the treatment of tuberculosis.

scholarly journals ABBV-744 as a potential inhibitor of SARS-CoV-2 main protease enzyme against COVID-19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zeynab Fakhar ◽  
Shama Khan ◽  
Suliman Y. AlOmar ◽  
Afrah Alkhuriji ◽  
Aijaz Ahmad
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Pharmacophore Modeling ◽  
Binding Energies ◽  
Active Inhibitor ◽  
Lead Compounds ◽  
Protease Enzyme ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Potential Inhibitors

AbstractA new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and become pandemic with thousands new deaths and infected cases globally. To address coronavirus disease (COVID-19), currently no effective drug or vaccine is available. This necessity motivated us to explore potential lead compounds by considering drug repurposing approach targeting main protease (Mpro) enzyme of SARS-CoV-2. This enzyme considered to be an attractive drug target as it contributes significantly in mediating viral replication and transcription. Herein, comprehensive computational investigations were performed to identify potential inhibitors of SARS-CoV-2 Mpro enzyme. The structure-based pharmacophore modeling was developed based on the co-crystallized structure of the enzyme with its biological active inhibitor. The generated hypotheses were applied for virtual screening based PhaseScore. Docking based virtual screening workflow was used to generate hit compounds using HTVS, SP and XP based Glide GScore. The pharmacological and physicochemical properties of the selected lead compounds were characterized using ADMET. Molecular dynamics simulations were performed to explore the binding affinities of the considered lead compounds. Binding energies revealed that compound ABBV-744 binds to the Mpro with strong affinity (ΔGbind −45.43 kcal/mol), and the complex is more stable in comparison with other protein–ligand complexes. Our study classified three best compounds which could be considered as promising inhibitors against main protease SARS-CoV-2 virus.

scholarly journals N,N’-Dialkyl-2-Thiobarbituric acid based Sulfonamides as potential SARS-CoV-2 main protease inhibitors

2021 ◽  
Author(s):  
Muhammad Sarfraz ◽  
Abdul Rauf ◽  
Paul A Keller ◽  
Ashfaq Mahmood Qureshi
Keyword(s):  
Protease Inhibitors ◽  
In Silico ◽  
Thiobarbituric Acid ◽  
Binding Energies ◽  
Ligand Efficiency ◽  
Lead Compounds ◽  
Protease Enzyme ◽  
Main Protease ◽  
Docking Energy ◽  
Better Than

An efficient methodology was developed to avail novel N,N’-dialkyl-2-thiobarbituric acid based sulfonamides S1-S4 in good to excellent yields (84-95%). The synthesized compounds S1-S4 were docked to screen their In-silico activities against two enzymes i.e. SARS-CoV-2 main protease enzyme with unliganded active site (2019-nCoV, coronavirus disease 2019, COVID-19) PDB ID: 6Y84 and SARS-CoV-2 Mpro PDB ID: 6LU7. Furthermore, some In-silico physicochemical and physicokinetic properties were evaluated using OSIRIS property explorer online, molinspiration property calculator, ADMET property calculator and GUSAR to assess these compounds as potential candidates as lead compounds for the quest of SARS- CoV-2 main protease inhibitors. Molecular docking analyses of the synthesized compounds predicted that compound S3 is more potent as SARS-CoV-2 main protease inhibitor with binding energy -11.65 Kcal/mol in comparison to reference inhibitor N3 (-10.95 Kcal/mol), whereas, compounds S1, S2 and S4 recorded comparable binding energies -9.89 Kcal/mol, -10.84 Kcal/mol and -10.94 Kcal/mol with reference inhibitor N3, however much better than remdesivir (-9.85 Kcal/mol). In case of SARS-CoV-2 Mpro, all compounds S1-S4 with docking energy values as -7.28, -8.38, -8.31 and -7.34 Kcal/mol were found potent in comparison to reference inhibitor N3 (-6.31 Kcal/mol) as well as remdesivir (-6.33 Kcal/mol). Ligand efficiency values against the target SARS-CoV-2 proteins as well as α-glucosidase and DNA-(apurinic or apyrimidinic site) lyase inhibition results of these newly synthesized compounds were also found promising.

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