Parameterization of Boronates Using VFFDT and Paramfit for Molecular Dynamics Simulation

Kurt, Barış; Temel, Hamdi

doi:10.3390/molecules25092196

Cited by 10 publications

(9 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The structure of Bovine Serum Albumin (BSA) was obtained from the Protein Data Bank (PDB ID: 4F5S, 2.47 Å). The structure of [B(Ph) 4 ] − (referred to as BPH for simplicity) was parameterized as by Kurt and Temel [38,39] and later built in xleap of AMBER16 package [40].…”

Section: Structuresmentioning

confidence: 99%

Effect of Tetraphenylborate on Physicochemical Properties of Bovine Serum Albumin

et al. 2021

View full text Add to dashboard Cite

The binding interactions of bovine serum albumin (BSA) with tetraphenylborate ions ([B(Ph)4]−) have been investigated by a set of experimental methods (isothermal titration calorimetry, steady-state fluorescence spectroscopy, differential scanning calorimetry and circular dichroism spectroscopy) and molecular dynamics-based computational approaches. Two sets of structurally distinctive binding sites in BSA were found under the experimental conditions (10 mM cacodylate buffer, pH 7, 298.15 K). The obtained results, supported by the competitive interactions experiments of SDS with [B(Ph)4]− for BSA, enabled us to find the potential binding sites in BSA. The first site is located in the subdomain I A of the protein and binds two [B(Ph)4]− ions (logK(ITC)1 = 7.09 ± 0.10; ΔG(ITC)1 = −9.67 ± 0.14 kcal mol−1; ΔH(ITC)1 = −3.14 ± 0.12 kcal mol−1; TΔS(ITC)1 = −6.53 kcal mol−1), whereas the second site is localized in the subdomain III A and binds five ions (logK(ITC)2 = 5.39 ± 0.06; ΔG(ITC)2 = −7.35 ± 0.09 kcal mol−1; ΔH(ITC)2 = 4.00 ± 0.14 kcal mol−1; TΔS(ITC)2 = 11.3 kcal mol−1). The formation of the {[B(Ph)4]−}–BSA complex results in an increase in the thermal stability of the alfa-helical content, correlating with the saturation of the particular BSA binding sites, thus hindering its thermal unfolding.

show abstract

Section: Structuresmentioning

confidence: 99%

Effect of Tetraphenylborate on Physicochemical Properties of Bovine Serum Albumin

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The obtained results were then used with the selenoglycosides as follows. The SeDG ligands were indeed parametrized using Gaussian 09 [ 19 ] and VFFDT [ 20 , 21 ] and an MD simulation of the ligand alone (free state) was performed to evaluate the stability of the ligand and possible parametrization errors. The results highlighted that in the free state, two different families for the ligand were observed, which differed in their adoption of an extended and V-shaped conformation.…”

Section: Resultsmentioning

confidence: 99%

Exploring the Molecular Interactions of Symmetrical and Unsymmetrical Selenoglycosides with Human Galectin-1 and Galectin-3

Pirone

Nieto-Fabregat

Gaetano

et al. 2022

IJMS

View full text Add to dashboard Cite

Galectins (Gals) are small cytosolic proteins that bind β-galactoside residues via their evolutionarily conserved carbohydrate recognition domain. Their dysregulation has been shown to be associated with many diseases. Consequently, targeting galectins for clinical applications has become increasingly relevant to develop tailored inhibitors selectively for one galectin. Accordingly, binding studies providing the molecular details of the interaction between galectin and inhibitor may be useful for the rational design of potent and selective antagonists. Gal-1 and Gal-3 are among the best-studied galectins, mainly for their roles in cancer progression; therefore, the molecular details of their interaction with inhibitors are demanded. This work gains more value by focusing on the interaction between Gal-1 and Gal-3 with the selenylated analogue of the Gal inhibitor thiodigalactose, characterized by a selenoglycoside bond (SeDG), and with unsymmetrical diglycosyl selenides (unsym(Se). Gal-1 and Gal-3 were produced heterologously and biophysically characterized. Interaction studies were performed by ITC, NMR spectroscopy, and MD simulation, and thermodynamic values were discussed and integrated with spectroscopic and computational results. The 3D complexes involving SeDG when interacting with Gal-1 and Gal-3 were depicted. Overall, the collected results will help identify hot spots for the design of new, better performing, and more specific Gal inhibitors.

show abstract

“…Perhaps this explains why there are not many examples of simulation studies involving ligands of this type. Herein, we have applied Seminario method ( Seminario, 1996 ) implemented in the Visual Force Field Derivation Toolkit (VFFDT) ( Zheng et al, 2016 ) and Paramfit programs recently reported ( Kurt and Temel, 2020 ). This approach was first validated by studying the QPX7728@OXA-48 enzyme complex for inactivation (Michaelis complex) and the subsequent QPX7728@OXA-48 enzyme adduct, and the latter was compared with the experimentally obtained (PDB ID 6V1O).…”

Section: Resultsmentioning

confidence: 99%

“…Boron parametrization was performed using the Seminario method ( Seminario, 1996 ) implemented in the VFFDT ( Zheng et al, 2016 ) and Paramfit programs ( Kurt and Temel, 2020 ). Usual GAFF atom types were applied to all atoms except for boron.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Basis of Bicyclic Boronate β-Lactamase Inhibitors of Ultrabroad Efficacy – Insights From Molecular Dynamics Simulation Studies

Lence

González‐Bello

2021

Front. Microbiol.

View full text Add to dashboard Cite

β-Lactam antibiotics represent about 70% of all antibacterial agents in clinical use. They are safe and highly effective drugs that have been used for more than 50 years, and, in general, well tolerated by most patients. However, its usefulness has been dramatically reduced with the spread and dissemination worldwide of multi-drug resistant bacteria. These pathogens elude the therapeutic action of these antibiotics by expressing β-lactamase enzymes that catalyze the hydrolysis of their β-lactam ring to give inactive products, which is one of the most relevant resistance mechanisms in deadly pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae. From the drug development point of view, the design of an efficient β-lactamase inhibitor able to block this antibiotic resistance mechanism and restore β-lactam antibiotics efficacy is challenging. This is due to: (1) the huge structural diversity of these enzymes in both the amino acid sequence and architecture of the active site; (2) the distinct hydrolytic capability against different types of substrates; (3) the variety of enzyme mechanisms of action employed, either involving covalent catalyzed processes (serine hydrolases) or non-covalent catalysis (zinc-dependent hydrolases); and (4) the increasing emergence and spread of bacterial pathogens capable of simultaneously producing diverse β-lactamases. Hence, a long-pursued goal has been the development of ultrabroad-spectrum inhibitors able to inhibit both serine- and metallo-β-lactamases. The recent development of taniborbactam (formerly VNRX-5133) and QPX7728, which are bicyclic boronate inhibitors currently under clinical development, represents a huge step forward in this goal. In this article, the molecular basis of the ultrabroad-spectrum of activity of these boron-based inhibitors is analyzed by molecular dynamics simulation studies using the available crystal structures in complex with both inhibitors, or the models constructed from wild-type forms. The efficacy of taniborbactam and QPX7728 is compared with the cyclic boronate inhibitor vaborbactam, which is the first boron-based β-lactamase inhibitor approved by the FDA in combination with meropenem for the treatment of complicated urinary tract infections.

show abstract

Parameterization of Boronates Using VFFDT and Paramfit for Molecular Dynamics Simulation

Cited by 10 publications

References 16 publications

Effect of Tetraphenylborate on Physicochemical Properties of Bovine Serum Albumin

Effect of Tetraphenylborate on Physicochemical Properties of Bovine Serum Albumin

Exploring the Molecular Interactions of Symmetrical and Unsymmetrical Selenoglycosides with Human Galectin-1 and Galectin-3

Molecular Basis of Bicyclic Boronate β-Lactamase Inhibitors of Ultrabroad Efficacy – Insights From Molecular Dynamics Simulation Studies

Contact Info

Product

Resources

About