Drug‐binding energetics of human α‐1‐acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations

Huang, Johnny X.; Cooper, Matthew A.; Baker, Mark A.; Azad, Mohammad Abul Kalam; Nation, Roger L.; Li, Jian; Velkov, Tony

doi:10.1002/jmr.2221

Cited by 26 publications

(18 citation statements)

References 70 publications

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“…The low stoichiometric ratio is also observed for Wrf, which has been reported to exhibit phenotype selectivity and to possess a stronger binding with the S-enantiomer for F1*S (Nakagawa et al, 2003). The enthalpyentropy compensation observed in our CAPs binding data is consistent with the thermodynamic data for basic small-molecule drugs recently reported by Huang et al, 2012. The low stoichiometric ratio observed in our binding data is however not previously described and thus differs from the small-molecule study.…”

Section: Isothermal Titration Calorimetrysupporting

confidence: 88%

“…The larger polymyxin antibiotics display a cyclic nonapeptidic backbone carrying several positive charges and are thus related to the shorter peptides studied in the present report even though the CAPs display an overall exothermic binding to AGP. The comprehensive small molecule study shows that ligands may bind to both AGP phenotypes with the same affinity, although the orientation of the bound molecule may differ as shown for chlorpromazine binding (Huang et al ., ). Whether this is possible for the larger CAPs was not established.…”

Section: Resultsmentioning

confidence: 97%

“…Compared with the two previous recent AGP studies reported by the Velkov group, a small molecule study and a comprehensive investigation of the binding of the polymyxin class of antibiotics to AGP (Azad et al ., ; Huang et al ., ), the main difference is that the currently studied CAPs utilize the binding site to a full extent instead of specific sub‐pockets. Whereas the small molecules are located in different sub‐pockets, the polymyxin class of antibiotics are interacting with their N‐terminal fatty acyl chain with the non‐polar residues of sub‐pocket I and III (Azad et al ., ).…”

Section: Resultsmentioning

confidence: 99%

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Short cationic antimicrobial peptides bind to human alpha‐1 acid glycoprotein with no implications for the in vitro bioactivity

Sivertsen

Brandsdal

Svendsen

et al. 2013

J of Molecular Recognition

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Several drugs interact with the major plasma proteins serum albumin and alpha-1 acid glycoprotein. Such binding may be either beneficial or disadvantageous from a pharmacokinetic perspective. In the present paper, we investigate the thermodynamics involved in the binding of a series of promising cationic antimicrobial peptides to the alpha-1 acid glycoprotein using isothermal titration calorimetry. The drug-like peptides are able to effectively destroy multiresistant bacterial strains, and members of this peptide class are currently in clinical phase II trials. Similar peptides, in a previous study, have been shown to bind to serum albumin resulting in a 10-fold reduction in the peptides ability to kill bacteria in vitro. Here, it is shown that the peptides also are ligands for alpha-1 glycoprotein with moderate binding affinities. The binding mode is investigated in detail using molecular docking, which maps the interaction to sub-pockets I, II and III of the binding site. Despite this interaction, protein binding is shown to have little or no effect on the ability of the peptides to kill bacteria in vitro, either at normal physiological or acute phase concentrations. The results show that although the peptides interact with the binding pocket of alpha-1 acid glycoprotein, the low stoichiometric binding ratio ensures that the interaction is not an obstacle for further development of these promising peptides as antimicrobial therapies.

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Section: Isothermal Titration Calorimetrysupporting

confidence: 88%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Short cationic antimicrobial peptides bind to human alpha‐1 acid glycoprotein with no implications for the in vitro bioactivity

Sivertsen

Brandsdal

Svendsen

et al. 2013

J of Molecular Recognition

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“…The a1-acid glycoprotein, an acute phase protein, is the principle extracellular lipocalin that plays an important role in the transport of hydrophobic compounds [22,23]. It is reported that a1-acid glycoprotein increases in HF patients [24].…”

Section: Discussionmentioning

confidence: 99%

The Efficacy of Tolvaptan in Congestive Heart Failure Patients with and Without Hypoalbuminemia: A Pilot Study

Okabe

Yakushiji

Igawa

et al. 2015

Cardiovascular Therapeutics

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SUMMARYBackground: Heart failure (HF) with hypoalbuminemia is associated with poor response to conventional therapy. We investigated whether tolvaptan, a potent aquaretic agent, might be of benefit in HF patients with hypoalbuminemia. Methods: We prospectively enrolled 40 patients hospitalized for HF. Patients received conventional therapy including loop diuretics. We subsequently added tolvaptan in the range of 3.75-15 mg daily and it was discontinued after improvement of HF symptoms. We compared clinical and laboratory data in HF patients with and without hypoalbuminemia (defined as serum albumin <3.0 g/ dL). Results: Tolvaptan was administered in 18 HF patients with hypoalbuminemia (Group A) and 22 HF patients without hypoalbuminemia (Group B). The mean serum albumin was 2.63 AE 0.27 and 3.46 AE 0.25 g/dL, respectively. The average urine output on tolvaptan increased significantly in both groups (1644.4 AE 797.6-3011.6 AE 1453.8 mL/day, P = 0.004; 1459 AE 612.7-2112.2 AE 724.5 mL/day, P = 0.008; respectively). In addition, we observed higher urine output on therapy in Group A than in Group B (P = 0.015). There was a moderate negative correlation between serum albumin and average urine output on tolvaptan (r = À0.42, P = 0.007). Conclusions: The addition of tolvaptan to low dose loop diuretics might be an effective strategy for treatment of HF patients with hypoalbuminemia.

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“…Hydrogen atoms were then added to the protein, and the structures of protein, ligand, and cofactor were combined in a single Macromodel file. The hydrogen atoms were minimized for 1000 steps with Macromodel in OPLS-AA force field, with all nonhydrogen atoms constrained to their original positions 13 . C. Docking Studies: The ligand-macromolecule interaction conformation is predicted and scored in terms of binding free energy between the ligand and macromolecule, have made a remarkable progress in their accuracy and speed, although molecular docking is an extremely demanding task for computer resources.…”

Section: A Finding Target Active Site and Ligandmentioning

confidence: 99%

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2013

IJPSR

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Malaria caused by the parasite Plasmodium falciparum is a major public health concern. The parasite lacks a functional Tricarboxylic acid cycle (TCA), making glycolysis its sole energy source. One such enzyme is triose phosphate isomerase. This catalyzes the isomerization of D-Glyceraldehyde 3 phosphate to dihydroxy acetone phosphate. An attempt was made to identify the potential phyto inhibitors and inhibit the enzyme as well as to modify their side chain to impure the binding efficiently. Here, two datasets are made such as training set and testing set, in which first, is training set, contain 19 known inhibitors against Triosephosphate Isomerase and second is testing set which contain 6 phyto-inhibitors to be tested. Autodock Vina, a docking tool, is used for molecular docking that utilizes information on conformational variability from ensembles of experimental receptor structure of Triosephosphate Isomerase. We showed that experimentally determined binding orientations and computed energies of known Ligands can be reproduced accurately. It also reported that the presence of phosphate groups in a ligand confers better stable docking.

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Drug‐binding energetics of human α‐1‐acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations

Cited by 26 publications

References 70 publications

Short cationic antimicrobial peptides bind to human alpha‐1 acid glycoprotein with no implications for the in vitro bioactivity

Short cationic antimicrobial peptides bind to human alpha‐1 acid glycoprotein with no implications for the in vitro bioactivity

The Efficacy of Tolvaptan in Congestive Heart Failure Patients with and Without Hypoalbuminemia: A Pilot Study

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