scholarly journals Phosphonic Analogues of Phenylglycine as Inhibitors of Aminopeptidases: Comparison of Porcine Aminopeptidase N, Bovine Leucine Aminopeptidase and Aminopeptidase from Barley Seeds

2019 ◽  
Author(s):  
Weronika Wanat ◽  
Michał Talma ◽  
Małgorzata Pawełczak ◽  
Paweł Kafarski
Keyword(s):  
Free Energy ◽  
Gibbs Free Energy ◽  
Aromatic Ring ◽  
Active Site ◽  
Inhibitory Activity ◽  
Leucine Aminopeptidase ◽  
Binding Mode ◽  
Aminopeptidase N ◽  
Zinc Ions ◽  
Similar Activity

Inhibitory activity of 14 phosphonic analogues of phenylglycine, substituted in aromatic ring by fluorine and chlorine, was determined towards porcine aminopeptidase N. The obtained data served as a basis for studying their interaction with the enzyme as modelled by the use of Schrödinger Release 2018 program. The observed linearity between modelled Gibbs free energy differences and inhibitory constants indicated the usefulness of this program. The obtained binding mode was compared with this modelled for bovine lens leucine aminopeptidase. Although both enzymes differ in the number of zinc ions present in the active site, they are considered to exhibit similar activity towards substrates and inhibitors. Our studies seem to support that  supposition since the modes of binding of the studied inhibitors are quite similar. Additionally, inhibitory activity of the phosphonic analogues of phenylglycine towards barley aminopetpidase was determined showing that this enzyme could be considered as neutral aminopeptidase.

scholarly journals Phosphonic Acid Analogues of Phenylglycine as Inhibitors of Aminopeptidases: Comparison of Porcine Aminopeptidase N, Bovine Leucine Aminopeptidase, Tomato Acidic Leucine Aminopeptidase and Aminopeptidase from Barley Seeds

2019 ◽  
Vol 12 (3) ◽  
pp. 139 ◽  
Author(s):  
Weronika Wanat ◽  
Michał Talma ◽  
Małgorzata Pawełczak ◽  
Paweł Kafarski
Keyword(s):  
Phosphonic Acid ◽  
Inhibitory Activity ◽  
Leucine Aminopeptidase ◽  
Aminopeptidase N ◽  
Binding Modes ◽  
Aromatic Rings ◽  
Phenyl Rings ◽  
The Difference ◽  
Uniform Manner ◽  
Highly Uniform

The inhibitory activity of 14 racemic phosphonic acid analogs of phenylglycine, substituted in aromatic rings, towards porcine aminopeptidase N (pAPN) and barley seed aminopeptidase was determined experimentally. The obtained patterns of the inhibitory activity against the two enzymes were similar. The obtained data served as a basis for studying the binding modes of these inhibitors by pAPN using molecular modeling. It was found that their aminophosphonate fragments were bound in a highly uniform manner and that the difference in their affinities most likely resulted from the mode of substitution of their phenyl rings. The obtained binding modes towards pAPN were compared, with these predicted for bovine lens leucine aminopeptidase (blLAP) and tomato acidic leucine aminopeptidase (tLAPA). The performed studies indicated that the binding manner of the phenylglycine analogs to biLAP and tLAPA are significantly similar and differ slightly from that predicted for pAPN.

scholarly journals Extending the Inhibition Profiles of Coumarin-Based Compounds Against Human Carbonic Anhydrases: Synthesis, Biological, and In Silico Evaluation

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3580 ◽  
Author(s):  
Kartsev ◽  
Geronikaki ◽  
Bua ◽  
Nocentini ◽  
Petrou ◽  
...  
Keyword(s):  
Active Site ◽  
Inhibitory Activity ◽  
Binding Mode ◽  
Carbonic Anhydrases ◽  
Reference Drug ◽  
Physiological Conditions ◽  
Computational Procedures ◽  
Living Organisms ◽  
Human Isoforms ◽  
Potent Inhibitory Activity

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets.

Synthesis and 4D-QSAR Studies of Alanine Hydroxamic Acid Derivatives as Aminopeptidase N Inhibitors

2019 ◽  
Vol 16 ◽  
Author(s):  
Min Gao ◽  
Qiao Li Lv ◽  
Hou Pan Zhang ◽  
Guo Gang Tu
Keyword(s):  
Biological Activity ◽  
Active Site ◽  
Hydroxamic Acid ◽  
Binding Mode ◽  
Qsar Model ◽  
Aminopeptidase N ◽  
Design Synthesis ◽  
Qsar Studies ◽  
Hydroxamic Acid Derivatives

Background: As a target for anticancer treatment, aminopeptidase N (APN) shows its overexpression on diverse malignant tumor cells and associates with cancer invasion, angiogenesis and metastasis. Objective: Design, synthesis and biological activity evaluation of alanine hydroxamic acid derivatives as APN inhibitors, and investigation the binding mode of inhibitors in the APN active site. Methods: Alanine hydroxamic acid derivatives were synthesized and evaluated for their in vitro anti-cancer activity using CCK-8 assay. Molecular docking and 4D-QSAR studies were carried out to suggest the mechanism of biological activity. Results: Compared with Bestatin, compound 9b showed the best APN inhibition activity. The putative binding mode of 9b in the APN active site was also discussed. Moreover, the robust and reliable 4D-QSAR model exhibited the following statistics: R2 = 0.9352, q2LOO = 0.8484, q2LNO =0.7920, R2Pred = 0.8739. Conclusion: Newly synthesized compounds exerted acceptable anticancer activity and further investigation on current scaffold would be beneficial.

Biological evaluation and docking studies of some benzoxazole derivatives as inhibitors of acetylcholinesterase and butyrylcholinesterase

2016 ◽  
Vol 71 (11-12) ◽  
pp. 409-413 ◽  
Author(s):  
Ozlem Temiz-Arpaci ◽  
Mustafa Arisoy ◽  
Duygu Sac ◽  
Fatima Doganc ◽  
Meryem Tasci ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Protein Interactions ◽  
Broad Spectrum ◽  
Active Site ◽  
Inhibitory Activity ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Molar Concentration ◽  
Reference Drug ◽  
Similar Activity

Abstract A series of 2,5-disubstituted-benzoxazole derivatives (1–13) were evaluated as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results demonstrated that the compounds exhibited a broad spectrum of AChE and BChE inhibitory activity ranging between 6.80% and 90.21% except one compound which showed no activity against AChE at the specified molar concentration. Another derivative displayed a similar activity to that of reference drug (galanthamine) for inhibition of AChE and BChE. In addition, molecular docking of the compounds into active site of AChE was performed using recombinant human AChE (PDB ID: 4ey6) in order to understand ligand–protein interactions.

scholarly journals Chromene-Containing Aromatic Sulfonamides with Carbonic Anhydrase Inhibitory Properties

2021 ◽  
Vol 22 (10) ◽  
pp. 5082
Author(s):  
Andrea Angeli ◽  
Victor Kartsev ◽  
Anthi Petrou ◽  
Mariana Pinteala ◽  
Volodymyr Brovarets ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Inhibitory Activity ◽  
Binding Mode ◽  
Carbonic Anhydrases ◽  
Inhibition Activity ◽  
Physiological Conditions ◽  
Computational Procedures ◽  
Living Organisms ◽  
Human Isoforms

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.

Characterization of an Abnormal Antithrombin (Milano 2) with Defective Thrombin Binding

1986 ◽  
Vol 56 (03) ◽  
pp. 349-352 ◽  
Author(s):  
A Tripodi ◽  
A Krachmalnicoff ◽  
P M Mannucci
Keyword(s):  
Venous Thromboembolism ◽  
Active Site ◽  
Inhibitory Activity ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Molecular Defect ◽  
Affinity Adsorption ◽  
Italian Family ◽  
Crossed Immunoelectrophoresis

SummaryFour members of an Italian family (two with histories of venous thromboembolism) had a qualitative defect of antithrombin III reflected by normal antigen concentrations and halfnormal antithrombin activity with or without heparin. Anti-factor Xa activities were consistently borderline low (about 70% of normal). For the propositus’ plasma and serum the patterns of antithrombin III in crossed-immunoelectrophoresis with or without heparin were indistinguishable from those of normal plasma or serum. A normal affinity of antithrombin III for heparin was documented by heparin-sepharose chromatography. Affinity adsorption of the propositus’ plasma to human α-thrombin immobilized on sepharose beads revealed defective binding of the anti thrombin III to thrombin-sepharose. Hence the molecular defect of this variant appears to be at the active site responsible for binding and neutralizing thrombin, thus accounting for the low thrombin inhibitory activity.

Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

2019 ◽  
Author(s):  
David Wright ◽  
Fouad Husseini ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Surface Area ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Binding Mode ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

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