Resolution of α/β-amino acids by enantioselective penicillin G acylase from Achromobacter sp .

Grulich, Michal; Brezovský, Jan; ŠtL·pánek, Václav; Palyzová, Andrea; Kyslíková, Eva; Kyslı́k, Pavel

doi:10.1016/j.molcatb.2015.09.008

Cited by 13 publications

(18 citation statements)

References 45 publications

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“…These comparisons were used to confirm that PTR1 is the target for the antileishmanial property of monastrol (authors also obtained confirmatory evidence by the PTR1 recombinant enzyme inhibition assay). In other work, Grulich et al [ 26 ] constructed the homology model of penicillin G acylase (PGA) from Achromobacter sp. and performed molecular docking using AutoDock Vina (La Jolla, CA, USA) to understand molecular basis of PGA enantioselectivity.…”

Section: Docking Binding Energy Predictions For Enantiomeric Drugsmentioning

confidence: 99%

Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

Ramírez

Caballero

2016

IJMS

133

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Molecular docking is a computational chemistry method which has become essential for the rational drug design process. In this context, it has had great impact as a successful tool for the study of ligand–receptor interaction modes, and for the exploration of large chemical datasets through virtual screening experiments. Despite their unquestionable merits, docking methods are not reliable for predicting binding energies due to the simple scoring functions they use. However, comparisons between two or three complexes using the predicted binding energies as a criterion are commonly found in the literature. In the present work we tested how wise is it to trust the docking energies when two complexes between a target protein and enantiomer pairs are compared. For this purpose, a ligand library composed by 141 enantiomeric pairs was used, including compounds with biological activities reported against seven protein targets. Docking results using the software Glide (considering extra precision (XP), standard precision (SP), and high-throughput virtual screening (HTVS) modes) and AutoDock Vina were compared with the reported biological activities using a classification scheme. Our test failed for all modes and targets, demonstrating that an accurate prediction when binding energies of enantiomers are compared using docking may be due to chance. We also compared pairs of compounds with different molecular weights and found the same results.

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Section: Docking Binding Energy Predictions For Enantiomeric Drugsmentioning

confidence: 99%

Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

Ramírez

Caballero

2016

IJMS

133

View full text Add to dashboard Cite

show abstract

“…Particularly, the challenges of molecular docking are the following: the prediction of ligands proper orientation, the prediction of the binding energies and the prediction of novel, effective drugs by using the structural knowledge obtained from the models [ 22 , 23 , 24 ]. Several examples using these computational methods have been already reported [ 23 , 24 , 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Secondary Metabolites in Ramalina terebrata Detected by UHPLC/ESI/MS/MS and Identification of Parietin as Tau Protein Inhibitor

Cornejo

Salgado

Caballero

et al. 2016

IJMS

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Liquid chromatography coupled with mass spectrometry is an outstanding methodology for fast analysis of phenolic compounds in biological samples. Twenty two compounds were quickly and accurately identified in the methanolic extract of the Antarctic lichen Ramalina terebrata for the first time using ultra high pressure liquid chromatography coupled with photodiode array detector and high resolution mass spectrometry (UHPLC-PDA-Q/Orbitrap/MS/MS). In addition, the extract and the four compounds isolated from this species were tested for the inhibitory activity of tau protein aggregation, which is a protein involved in Alzheimer’s disease (AD). All compounds showed null activity with the exception of parietin, which it was able to inhibit aggregation process of tau in a concentration range between 3 µg/mL (10 µM) to 28 µg/mL (100 µM). In addition, we show how parietin interact with tau 306VQIVYK311 hexapeptide inside of the microtubule binding domain (4R) with the help of molecular docking experiments. Finally, the constituents present in the methanolic extract could possibly contribute to the established anti-aggregation activity for this extract and this in-depth analysis of the chemical composition of R. terebrata could guide further research into its medicinal properties and potential uses.

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“…These criteria were used to promote proper orientation of the hydroxyl hydrogen of the nucleophilic serine relative to its amine group, which serves as a hydrogen acceptor in the first reaction step, and to ensure appropriate pre-organization of the catalytic machinery (i.e., the nucleophile serine and the oxyanion hole stabilizing residues) for reactive binding of the substrate. 53,57,69,70…”

Section: Methodsmentioning

confidence: 99%

Common Dynamic Determinants Govern Quorum Quenching Activity in N-terminal Serine Hydrolases

Surpeta

Grulich

Palyzová

et al. 2022

Preprint

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Due to the alarming global crisis of the growing microbial antibiotic resistance, investigation of alternative strategies to combat this issue has gained considerable momentum in the recent decade. A quorum quenching (QQ) process disrupts bacterial communication through so-called quorum sensing that enables bacteria to sense the cell density in the surrounding environment. Due to its indirect mode of action, QQ is believed to exert limited pressure on essential bacterial functions and consequently avoid inducing resistance. Although many enzymes are known to display the QQ activity towards various molecules used for bacterial signaling, the in-depth mechanism of their action is not well understood hampering their possible optimization for such exploitation. In this study, we compare the potential of three members of N-terminal serine hydrolases to degrade N-acyl homoserine lactones--signaling compounds employed by Gram-negative bacteria. Using molecular dynamics simulation of free enzymes and their complexes with two signaling molecules of different lengths, followed by quantum mechanics/molecular mechanics molecular dynamics simulation of their initial catalytic steps, we explored molecular details behind their QQ activities. We observed that all three enzymes were able to degrade bacterial signaling molecules following an analogous reaction mechanism. For the two investigated penicillin G acylases from Escherichia coli (ecPGA) and Achromobacter spp. (aPGA), we confirmed their putative activities experimentally hereby extending the set of known quorum quenching enzymes by these representatives of biotechnologically well-optimized enzymes. Interestingly, we detected enzyme- and substrate-depended differences among the three enzymes caused primarily by the distinct structure and dynamics of acyl-binding cavities. As a consequence, the first reaction step catalyzed by ecPGA with a longer substrate exhibited an elevated energy barrier due to a too shallow acyl-binding site incapable of accomodating this molecule in a required configuration. Conversely, unfavorable energetics on both reaction steps were observed for aPGA in complex with both substrates, conditioned primarily by the increased dynamics of the residues gating the entrance to the acyl-binding cavity. Finally, the energy barriers of the second reaction step catalyzed by Pseudomonas aeruginosa acyl-homoserine lactone acylase with both substrates were higher than in the other two enzymes due to distinct positioning of Arg297β. These discovered dynamic determinants constitute valuable guidance for further research towards designing robust QQ agents capable of selectively controlling the virulence of resistant bacteria species.

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Resolution of α/β-amino acids by enantioselective penicillin G acylase from Achromobacter sp .

Cited by 13 publications

References 45 publications

Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

Secondary Metabolites in Ramalina terebrata Detected by UHPLC/ESI/MS/MS and Identification of Parietin as Tau Protein Inhibitor

Common Dynamic Determinants Govern Quorum Quenching Activity in N-terminal Serine Hydrolases

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