scholarly journals Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2875
Author(s):  
Richelly Cardoso ◽  
Renan Valente ◽  
Clauber Henrique Souza da Costa ◽  
João Lidio da S. Gonçalves Vianez ◽  
Kauê Santana da Costa ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Active Site ◽  
Kojic Acid ◽  
Copper Ion ◽  
Aromatic Aldehydes ◽  
Free Energies ◽  
Modeling Tools ◽  
Enzyme Active Site ◽  
Competitive Inhibitors ◽  
Binding Free Energies

Tyrosinases belong to the functional copper-containing proteins family, and their structure contains two copper atoms, in the active site, which are coordinated by three histidine residues. The biosynthesis of melanin in melanocytes has two stages depending on the actions of the natural substrates L-DOPA and L-tyrosine. The dysregulation of tyrosinase is involved in skin cancer initiation. In the present study, using molecular modeling tools, we analyzed the inhibition activity of tyrosinase activity using kojic acid (KA) derivatives designed from aromatic aldehydes and malononitrile. All derivatives showed conformational affinity to the enzyme active site, and a favorable distance to chelate the copper ion, which is essential for enzyme function. Molecular dynamics simulations revealed that the derivatives formed promising complexes, presenting stable conformations with deviations between 0.2 and 0.35 Å. In addition, the investigated KA derivatives showed favorable binding free energies. The most stable KA derivatives showed the following binding free energies: −17.65 kcal mol−1 (D6), −18.07 kcal mol−1 (D2), −18.13 (D5) kcal mol−1, and −10.31 kcal mol−1 (D4). Our results suggest that these derivatives could be potent competitive inhibitors of the natural substrates of L-DOPA (−12.84 kcal mol−1) and L-tyrosine (−9.04 kcal mol−1) in melanogenesis.

Non-Stick Sugars: Synthesis of Difluorosugar Fluorides as Potential Glycosidase Inactivators

2009 ◽  
Vol 62 (6) ◽  
pp. 590 ◽  
Author(s):  
Brian P. Rempel ◽  
Stephen G. Withers
Keyword(s):  
Active Site ◽  
Time Dependent ◽  
Enzyme Active Site ◽  
Radical Bromination ◽  
Dependent Inactivation ◽  
Competitive Inhibitors

Four new difluorosugar fluorides, 2-deoxy-2,5-difluoro-α-l-idopyranosyl fluoride, 1,5-difluoro-d-glucopyranosyl fluoride, 1,5-difluoro-l-idopyranosyl fluoride, and 2-deoxy-1,2-difluoro-d-glucopyranosyl fluoride, were synthesized from known precursors by a radical bromination/fluoride displacement sequence, followed by deprotection. The compounds were tested as time-dependent inactivators of the β-glucosidase from Agrobacterium sp. (Abg, EC 3.2.1.21) and, while they were shown to bind to the enzyme active site as reversible competitive inhibitors, the only time-dependent inactivation observed was traced to the presence of an extremely small amount (<0.1%) of a highly reactive contaminating impurity.

Dissection of HIV-1 Protease Subtype B Inhibitors Resistance Through Molecular Modeling Approaches

2018 ◽  
pp. 149-170
Author(s):  
Ameeruddin Nusrath Unissa ◽  
Luke Elizabeth Hanna
Keyword(s):  
Active Site ◽  
Tight Binding ◽  
Viral Gene ◽  
Enzyme Active Site ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Competitive Inhibitors ◽  
Hiv 1 ◽  
Important Enzyme

Protease (PR) is an important enzyme required for the posttranslational processing of the viral gene products of type-1 human immunodeficiency virus (HIV-1). Protease inhibitors (PI) act as competitive inhibitors that bind to the active site of PR. The I84V mutation contributes resistance to multiple PIs, and structurally, this mutation affects both sides of the enzyme active site. In order to get insights about this major resistance site to PR inhibitors using in silico approaches, in this chapter, the wild-type (WT) and mutant (MT) I84V of PR were modeled and docked with all PR inhibitors: Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Saquinavir, and Tipranavir. Docking results revealed that in comparison to the WT, the binding score was higher for the MT-I84V. Thus, it can be suggested that the high affinity towards inhibitors in the MT could be due to the presence of energetically favorable interactions, which may lead to tight binding of inhibitors with the MT protein, leading to the development of PR resistance against PIs in HIV-1 eventually.

scholarly journals Purification and identification of metabolites produced by Bacillus cereus and B. subtilis active against Meloidogyne exigua, and their in silico interaction with a putative phosphoribosyltransferase fromM. incognita

2014 ◽  
Vol 86 (2) ◽  
pp. 525-538 ◽  
Author(s):  
DENILSON F. OLIVEIRA ◽  
HELVÉCIO M. DOS SANTOS JÚNIOR ◽  
ALEXANDRO S. NUNES ◽  
VICENTE P. CAMPOS ◽  
RENATA S.C. DE PINHO ◽  
...  
Keyword(s):  
Bacillus Cereus ◽  
Active Site ◽  
In Silico ◽  
Parasitic Nematode ◽  
Free Energies ◽  
Similar Sequence ◽  
Dynamics Simulations ◽  
Plant Parasitic ◽  
Selection Of ◽  
Binding Free Energies

To contribute to the development of products to controlMeloidogyne exigua, the bacteria Bacillus cereus and B. subtilis were cultivated in liquid medium to produce metabolites active against this plant-parasitic nematode. Fractionation of the crude dichloromethane extracts obtained from the cultures afforded uracil, 9H-purine and dihydrouracil. All compounds were active against M. exigua, the latter being the most efficient. This substance presented a LC50 of 204 µg/mL against the nematode, while a LC50 of 260 µg/mL was observed for the commercial nematicide carbofuran. A search for protein-ligand complexes in which the ligands were structurally similar to dihydrouracil resulted in the selection of phosphoribosyltransferases, the sequences of which were used in an in silico search in the genome of M. incognita for a similar sequence of amino acids. The resulting sequence was modelled and dihydrouracil and 9H-purine were inserted in the active site of this putative phosphoribosyltransferase resulting in protein-ligand complexes that underwent molecular dynamics simulations. Calculation of the binding free-energies of these complexes revealed that the dissociation constant of dihydrouracil and 9H-purine to this protein is around 8.3 x 10-7 and 1.6 x 10-6 M, respectively. Consequently, these substances and the putative phosphoribosyltransferase are promising for the development of new products to control M. exigua.

Synthesis, Molecular Modeling and Biological Evaluation of 5-arylidene-N,N-diethylthiobarbiturates as Potential α-glucosidase Inhibitors

2019 ◽  
Vol 15 (2) ◽  
pp. 175-185 ◽  
Author(s):  
Momin Khan ◽  
Sehrish Khan ◽  
Amir Ul Mulk ◽  
Anis Ur Rahman ◽  
Abdul Wadood ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Barbituric Acid ◽  
Aromatic Aldehydes ◽  
Biological Evaluation ◽  
Distilled Water ◽  
Sound Effects ◽  
Glucosidase Inhibitors ◽  
Ic50 Values ◽  
Antiviral Activities ◽  
Barbituric Acid Derivatives

Background:Barbituric acid derivatives are a versatile group of compounds which are identified as potential pharmacophores for the treatment of anxiety, epilepsy and other psychiatric disorders. They are also used as anesthetics and have sound effects on the motor and sensory functions. Barbiturates are malonylurea derivatives with a variety of substituents at C-5 position showing resemblance with nitrogen and sulfur containing compounds like thiouracil which exhibited potent anticancer and antiviral activities. Recently, barbituric acid derivatives have also received great interest for applications in nanoscience.Objective:Synthesis of 5-arylidene-N,N-diethylthiobarbiturates, biological evaluation as potential α-glucosidase inhibitors and molecular modeling.Methods:In the present study, N,N-Diethylthiobarbituric acid derivatives were synthesized by refluxing of N,N-diethylthiobarbituric acid and different aromatic aldehydes in distilled water. In a typical reaction; a mixture of N,N-diethylthiobarbituric acid 0.20 g (1 mmol) and 5-bromo-2- hydroxybenzaldehyde 0.199 g (1 mmol) mixed in 10 mL distilled water and reflux for 30 minutes. After completion of the reaction, the corresponding product 1 was filtered and dried and yield calculated. It was crystallized from ethanol. The structures of synthesized compounds 1-25 were carried out by using 1H, 13C NMR, EI spectroscopy and CHN analysis used for the determination of their structures. The α-glucosidase inhibition assay was performed as given by Chapdelaine et al., with slight modifications and optimization.Results:Our newly synthesized compounds showed a varying degree of α-glucosidase inhibition and at least four of them were found as potent inhibitors. Compounds 6, 5, 17, 11 exhibited IC50 values (Mean±SEM) of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 µM, respectively, as compared to standard acarbose (IC50, 38.25 ± 0.12 µM).Conclusion:Our present study has shown that compounds 6, 5, 17, 11 exhibited IC50 values of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 µM, respectively. The studies were supported by in silico data analysis.

scholarly journals Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Germano Heinzelmann ◽  
Michael K. Gilson
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Low Cost ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Drug Candidates ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

AbstractAbsolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.

scholarly journals Protein-ligand free energies of binding from full-protein DFT calculations: convergence and choice of exchange-correlation functional

2021 ◽  
Author(s):  
Lennart Gundelach ◽  
Christofer S Tautermann ◽  
Thomas Fox ◽  
Chris-Kriton Skylaris
Keyword(s):  
Drug Discovery ◽  
Ligand Binding ◽  
Dft Calculations ◽  
Quantum Mechanical ◽  
Free Energies ◽  
Ligand Interaction ◽  
Exchange Correlation ◽  
Ligand Free ◽  
Protein Ligand Interaction ◽  
Binding Free Energies

The accurate prediction of protein-ligand binding free energies with tractable computational methods has the potential to revolutionize drug discovery. Modeling the protein-ligand interaction at a quantum mechanical level, instead of...

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