Simultaneous molecular docking of different ligands to His6-tagged organophosphorus hydrolase as an effective tool for assessing their effect on the enzyme

Background Enzymatic hydrolysis of N-acyl homoserine lactones (AHLs), which are signaling molecules responsible for the development of antibiotic resistance in gram-negative bacteria, is a potential solution to overcoming antibiotic resistance problem. It has been established that hexahistidine-tagged organophosphorus hydrolase (His6-OPH) exhibits lactonase activity against a number of AHLs and that the combined application of His6-OPH with β-lactam antibiotics leads to an increase in the efficiency of the action of both the enzyme and antibiotics. The use of computational methods can be an effective way to search for and select from the known antibiotics to find the most rational “partners” for combining with this enzyme and creating effective antibacterial agents with a dual (lactonase and antibacterial) functional activity. Methods In this study, by using AutoDock Vina and Gromacs softwares the molecular docking and the molecular dynamics methods were adopted to simulate models of puromycin, ceftiofur, and/or AHLs docked to the surface of a dimer molecule of His6-OPH and to study their binding properties. GABEDIT and GAMESS-US packages were used to generate and simulate electron densities of docked AHLs. Results Interactions of N-butyryl-DL-homoserine lactone (C4-HSL), N-(3-oxooctanoyl)-L-homoserine lactone (C8-HSL) and N-(3-oxododecanoyl)-L-homoserine lactone (C12-HSL) with His6-OPH dimer active sites in the presence of puromycin and ceftiofur were simulated and studied. The possible intersection of long-chain AHLs with antibiotic molecules in the active sites of the enzyme was revealed. The binding energies of antibiotics and AHLs with the His6-OPH surface were estimated. Statistically significant differences (p = 0.003) were observed between the values calculated for both C4-HSL and C12-HSL, whereas there were no statistically significant differences between the values of the other groups (p ≥ 0.100). The binding energies of AHLs with His6-OPH were slightly higher as compared with the binding energies of antibiotics with the enzyme. The dynamics of the most probable models obtained from docking were investigated. RMSD and RMSF analysis of His6-OPH-AHL complexes in the absence and presence of antibiotics were performed. The interaction energy values of antibiotics and AHLs with the His6-OPH were assessed. Significant increase of the AHLs steadiness in enzyme-substrate complexes in the presence of antibiotics was revealed. The interaction between His6-OPH and C12-HSL was established as thermodynamically more favored. Conclusions It has been established that the studied antibiotics puromycin and ceftiofur steady the enzyme-substrate complexes, but at the same time lead to a decrease in the long-chain AHL-hydrolytic activity of His6-OPH in such a combination as compared to a native enzyme, and, therefore, it should be taken into account when creating a therapeutic composition based on combining antibiotics with His6-OPH.

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Mechanochemical Synthesis, in vitro Evaluation and Molecular Docking Studies of 4-Amino-2-arylamino-5-(benzofuran-2-oyl)thiazoles as Antidiabetic Agents

Letters in Organic Chemistry ◽

10.2174/1570178615666180815124425 ◽

2019 ◽

Vol 16 (7) ◽

pp. 560-568

Author(s):

Vijayan R. Akhila ◽

Maheswari R. Priya ◽

Daisy R. Sherin ◽

Girija K. Krishnapriya ◽

Sreerekha V. Keerthi ◽

...

Keyword(s):

Molecular Docking ◽

Mechanochemical Synthesis ◽

Active Sites ◽

Docking Studies ◽

Binding Energies ◽

Antidiabetic Activity ◽

Antidiabetic Agents ◽

Molecular Docking Studies ◽

Ic50 Value

The synthesis of 4-amino-2-arylamino-5-(benzofuran-2-oyl)thiazoles 4a-h, as example of 2,4-diaminothiazole-benzofuran hybrids and an evaluation of their antidiabetic activity, by in vitro and computational methods, are reported. The synthesis of these diaminothiazoles was achieved mechano chemically by a rapid solvent-less method. Their antidiabetic activity was assessed by α-glucosidase and α-amylase inhibition assays. The, IC50 value for α-glucosidase inhibition by 4-amino-5- (benzofuran-2-oyl)-2-(4-methoxyphenylamino)thiazole (4d) was found to be 20.04 µM and the IC50 value for α-amylase inhibition, 195.03 µM, whereas the corresponding values for reference acarbose were 53.38 µM and 502.03 µM, respectively. Molecular docking studies at the active sites of α- glucosidase and α-amylase showed that among the diaminothiazoles 4a-h now studied, 4-amino-5- (benzofuran-2-oyl)-2-(4-methoxyphenylamino)thiazole (4d) has the highest D-scores of -8.63 and -8.08 for α-glucosidase and for α-amylase, with binding energies -47.76 and -19.73 kcal/mol, respectively.

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Structure and mechanism of potent bifunctional β-lactam- and homoserine lactone-degrading enzymes from marine microorganisms

10.1101/2020.03.24.006742 ◽

2020 ◽

Author(s):

Christopher Selleck ◽

Marcelo Monteiro Pedroso ◽

Liam Wilson ◽

Stephan Krco ◽

Esmée Gianna Knaven ◽

...

Keyword(s):

Health Care ◽

Antibiotic Resistance ◽

Resistance Genes ◽

Reaction Mechanisms ◽

Active Sites ◽

Homoserine Lactone ◽

Pathogenic Microorganisms ◽

Marine Microorganisms ◽

Bacterial Strains ◽

Fast Kinetics

AbstractGenes that confer antibiotic resistance can rapidly be disseminated from one microorganism to another by mobile genetic elements, thus transferring resistance to previously susceptible bacterial strains. The misuse of antibiotics in health care and agriculture has provided a powerful evolutionary pressure to accelerate the spread of resistance genes, including those encoding β-lactamases. These are enzymes that are highly efficient in inactivating most of the commonly used β-lactam antibiotics. However, genes that confer antibiotic resistance are not only associated with pathogenic microorganisms, but are also found in non-pathogenic (i.e. environmental) microorganisms. Two recent examples are metal-dependent β-lactamases (MBLs) from the marine organisms Novosphingobium pentaromativorans and Simiduia agarivorans. Previous studies have demonstrated that their β-lactamase activity is comparable to those of well-known MBLs from pathogenic sources (e.g. NDM-1, AIM-1) but that they also possess efficient lactonase activity, an activity associated with quorum sensing. Here, we probed the structure and mechanism of these two enzymes using crystallographic, spectroscopic and fast kinetics techniques. Despite highly conserved active sites both enzymes demonstrate significant variations in their reaction mechanisms, highlighting both the extraordinary ability of MBLs to adapt to changing environmental conditions and the rather promiscuous acceptance of diverse substrates by these enzymes.

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Identification of Persuasive Antiviral Natural Compounds for COVID-19 by Targeting Endoribonuclease NSP15: A Structural-Bioinformatics Approach

Molecules ◽

10.3390/molecules25235657 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5657

Author(s):

Mohd Saeed ◽

Amir Saeed ◽

Md Jahoor Alam ◽

Mousa Alreshidi

Keyword(s):

Molecular Docking ◽

Life Cycle ◽

High Throughput Screening ◽

Active Sites ◽

Rna Virus ◽

Natural Compounds ◽

Binding Energies ◽

Dynamics Simulation ◽

Active Site Residues ◽

Nonstructural Proteins

SARS-CoV-2 is a positive-stranded RNA virus that bundles its genomic material as messenger-sense RNA in infectious virions and replicates these genomes through RNA intermediates. Several virus-encoded nonstructural proteins play a key role during the viral life cycle. Endoribonuclease NSP15 is vital for the replication and life cycle of the virus, and is thus considered a compelling druggable target. Here, we performed a combination of multiscoring virtual screening and molecular docking of a library of 1624 natural compounds (Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database) on the active sites of NSP15 (PDB:6VWW). After sequential high-throughput screening by LibDock and GOLD, docking optimization by CDOCKER, and final scoring by calculating binding energies, top-ranked compounds NuBBE-1970 and NuBBE-242 were further investigated via an indepth molecular-docking and molecular-dynamics simulation of 60 ns, which revealed that the binding of these two compounds with active site residues of NSP15 was sufficiently strong and stable. The findings strongly suggest that further optimization and clinical investigations of these potent compounds may lead to effective SARS-CoV-2 treatment.

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Novel approach to quorum quenching: rational design of antibacterials in combination with hexahistidine-tagged organophosphorus hydrolase

Biological Chemistry ◽

10.1515/hsz-2018-0162 ◽

2018 ◽

Vol 399 (8) ◽

pp. 869-879 ◽

Cited By ~ 8

Author(s):

Aysel Aslanli ◽

Ilya Lyagin ◽

Elena Efremenko

Keyword(s):

Molecular Docking ◽

Rational Design ◽

Pathogenic Bacteria ◽

Quorum Quenching ◽

Homoserine Lactone ◽

Catalytic Action ◽

Organophosphorus Hydrolase ◽

Signal Molecules ◽

Bacterial Strains ◽

Native Form

Abstract N-acyl homoserine lactones (AHLs) are quorum sensing (QS) signal molecules used by most Gram-negative pathogenic bacteria. In this article the lactonase activity of the preparations based on hexahistidine-tagged organophosphorus hydrolase (His6-OPH) towards AHLs was studied. Initially, three of the most interesting β-lactam antibiotics were selected from seven that were trialed during molecular docking to His6-OPH. Combinations of antibiotics (meropenem, imipenem, ceftriaxone) and His6-OPH taken in the native form or in the form of non-covalent enzyme-polyelectrolyte complexes (EPCs) with poly(glutamic acid) or poly(aspartic acid) were obtained and investigated. The lactonase activity of the preparations was investigated under different physical-chemical conditions in the hydrolysis of AHLs [N-butyryl-D,L-homoserine lactone, N-(3-oxooctanoyl)-D,L-homoserine lactone, N-(3-oxododecanoyl)-L-homoserine lactone]. An increased efficiency of catalytic action and stability of the lactonase activity of His6-OPH was shown for its complexes with antibiotics and was confirmed in trials with bacterial strains. The broadening of the catalytic action of the enzyme against AHLs was revealed in the presence of the meropenem. Results of molecular docking of AHLs to the surface of the His6-OPH dimer in the presence of antibiotics allowed proposing the mechanism of such interference based on a steric repulsion of the carbon chain of hydrolyzed AHLs by the antibiotics bounded to the enzyme surface.

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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 ◽

10.3390/molecules26247458 ◽

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.

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On the Adsorption of Aspartate Derivatives to Calcite Surfaces in Aqueous Environment

10.26434/chemrxiv.11558430.v1 ◽

2020 ◽

Author(s):

Robert Stepic ◽

Lara Jurković ◽

Ksenia Klementyeva ◽

Marko Ukrainczyk ◽

Matija Gredičak ◽

...

Keyword(s):

Active Sites ◽

Realistic Model ◽

Binding Energies ◽

Inhibition Mechanism ◽

Aqueous Environment ◽

Binding Modes ◽

Carboxylate Groups ◽

Dissolved Ions ◽

Living Organisms ◽

Dynamics Simulations

In many living organisms, biomolecules interact favorably with various surfaces of calcium carbonate. In this work, we have considered the interactions of aspartate (Asp) derivatives, as models of complex biomolecules, with calcite. Using kinetic growth experiments, we have investigated the inhibition of calcite growth by Asp, Asp2 and Asp3.This entailed the determination of a step-pinning growth regime as well as the evaluation of the adsorption constants and binding free energies for the three species to calcite crystals. These latter values are compared to free energy profiles obtained from fully atomistic molecular dynamics simulations. When using a flat (104) calcite surface in the models, the measured trend of binding energies is poorly reproduced. However, a more realistic model comprised of a surface with an island containing edges and corners, yields binding energies that compare very well with experiments. Surprisingly, we find that most binding modes involve the positively charged, ammonium group. Moreover, while attachment of the negatively charged carboxylate groups is also frequently observed, it is always balanced by the aqueous solvation of an equal or greater number of carboxylates. These effects are observed on all calcite features including edges and corners, the latter being associated with dominant affinities to Asp derivatives. As these features are also precisely the active sites for crystal growth, the experimental and theoretical results point strongly to a growth inhibition mechanism whereby these sites become blocked, preventing further attachment of dissolved ions and halting further growth.

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Dose COVID-19 Uncovered a New Feature of Metronidazole Drug?

10.26434/chemrxiv.12526277.v2 ◽

2020 ◽

Author(s):

Mohammad Seyedhamzeh ◽

Bahareh Farasati Far ◽

Mehdi Shafiee Ardestani ◽

Shahrzad Javanshir ◽

Fatemeh Aliabadi ◽

...

Keyword(s):

Molecular Docking ◽

Drug Discovery ◽

Virtual Screening ◽

Active Sites ◽

Initial Plasma ◽

New Feature ◽

Metronidazole Benzoate ◽

Global Health Problem ◽

A Current ◽

Pro Inflammatory Cytokines

Studies of coronavirus disease 2019 (COVID-19) as a current global health problem shown the initial plasma levels of most pro-inflammatory cytokines increased during the infection, which leads to patient countless complications. Previous studies also demonstrated that the metronidazole (MTZ) administration reduced related cytokines and improved treatment in patients. However, the effect of this drug on cytokines has not been determined. In the present study, the interaction of MTZ with cytokines was investigated using molecular docking as one of the principal methods in drug discovery and design. According to the obtained results, the IL12-metronidazole complex is more stable than other cytokines, and an increase in the surface and volume leads to prevent to bind to receptors. Moreover, ligand-based virtual screening of several libraries showed metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5- nitroimidazol-2-yl]-N-methylmethanimine oxide, acyclovir, and tetrahydrobiopterin (THB or BH4) like MTZ by changing the surface and volume prevents binding IL-12 to the receptor. Finally, the inhibition of the active sites of IL-12 occurred by modifying the position of the methyl and hydroxyl functional groups in MTZ.

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In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

10.26434/chemrxiv.12480434.v1 ◽

2020 ◽

Author(s):

Sahar Qazi ◽

Mustafa Alhaji Isa ◽

Adam Mustapha ◽

Khalid Raza ◽

Ibrahim Alkali Allamin ◽

...

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

Anacardium Occidentale ◽

Upper Respiratory Tract ◽

Ligand Complex ◽

In Silico Docking ◽

Main Protease

The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of Zingiber offinale and Anacardium occidentale using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of Zingiber offinale and the leaves of Anacardium occidentale. These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), Pan-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907).

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In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

10.26434/chemrxiv.12480434 ◽

2020 ◽

Author(s):

Sahar Qazi ◽

Mustafa Alhaji Isa ◽

Adam Mustapha ◽

Khalid Raza ◽

Ibrahim Alkali Allamin ◽

...

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

Anacardium Occidentale ◽

Upper Respiratory Tract ◽

Ligand Complex ◽

In Silico Docking ◽

Main Protease

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1'-methylspiro[indoline-3,4'-piperidine] Derivatives: Design, Synthesis, Molecular Docking and Anti-tumor Activity Studies

Letters in Drug Design & Discovery ◽

10.2174/1570180817999201117150714 ◽

2020 ◽

Vol 17 ◽

Author(s):

Junjian Li ◽

Lianbao Ye ◽

Yuanyuan Wang ◽

Ying Liu ◽

Xiaobao Jin ◽

...

Keyword(s):

Molecular Docking ◽

Cell Lines ◽

Active Sites ◽

Biological Activities ◽

Significant Inhibition ◽

Alkaline Condition ◽

Discovery Studio ◽

Hela Cell Lines ◽

Antiproliferative Activities

Background: Spirocyclic indoline compounds widely exist in numerous natural products with good biological activities and some drug molecules in many aspects. In recent years, it has attracted extensive attention as potent anti-tumor agents in the fields of pharmacology and chemistry. Objective: In this study, we focused on designing and synthesizing a set of novel 1'-H-spiro[indole-3,4'-piperidine] derivatives, which were evaluated by preliminary bioactivity experiment in vitro and molecular docking. Method: The key intermediate 1'-methylspiro[indoline-3,4'-piperidine] (B4) reacted with benzenesulfonyl chloride with different substituents under alkaline condition to obtain its sulfonyl derivatives (B5-B10). We evaluated their antiproliferative activities against A549, BEL-7402 and HeLa cells by MTT assay. We performed the CDOCKER module in Discovery Studio 2.5.5 software for molecular modeling of compound B5, and investigated the binding of compound B5 with the target proteins from PDB database. Results: The results indicated that compounds B4-B10 exhibited good antiproliferative activities against the above three types of cells, in which compound B5 with chloride atom as electron-withdrawing substituent on a phenyl ring showed the highest potency against BEL-7402 cells (IC50=30.03±0.43 μg/mL). By binging of the prominent bioactive compound B5 to CDK, c-Met, EGFR protein crystals, The binding energy of B5 with these three types receptors are -44.3583 kcal/mol, - 38.3292 kcal/mol, -33.3653 kcal/mol respectively. Conclusion: Six 1'-methylspiro[indoline-3,4'-piperidine] derivatives were synthesized and evaluated against BEL-7402, A- 549, HeLa cell lines. Compound B5 showed significant inhibition on BEL-7402 cell lines. Molecular docking revealed that B5 showed good affinity by the good fitting between B5 and these three targets with amino acid residues in active sites which encourage us to conduct further evaluation such as the kinase experiment.

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