The molecular basis of urokinase inhibition: from the nonempirical analysis of intermolecular interactions to the prediction of binding affinity |
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Authors: | Renata Grzywa Edyta Dyguda-Kazimierowicz Marcin Sieńczyk Mikołaj Feliks W Andrzej Sokalski Józef Oleksyszyn |
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Institution: | (1) Department of Chemistry, Wrocław University of Technology, Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland |
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Abstract: | Urokinase-type plasminogen activator (uPA) is a trypsin-like serine protease that plays a crucial role in angiogenesis process.
In addition to its physiological role in healthy organisms, angiogenesis is extremely important in cancer growth and metastasis,
resulting in numerous attempts to understand its control and to develop new approaches to anticancer therapy. The α-aminoalkylphosphonate
diphenyl esters are well known as highly efficient serine protease inhibitors. However, their mode of binding has not been
verified experimentally in details. For a group of average and potent phosphonic inhibitors of urokinase, flexible docking
calculations were performed to gain an insight into the active site interactions responsible for observed enzyme inhibition.
The docking results are consistent with the previously suggested mode of inhibitors binding. Subsequently, rigorous ab initio
study of binding energy was carried out, followed by its decomposition according to the variation–perturbation procedure to
reveal stabilization energy constituents with clear physical meaning. Availability of the experimental inhibitory activities
and comparison with theoretical binding energy allows for the validation of theoretical models of inhibition, as well as estimation
of the possible potential for binding affinity prediction. Since the docking results accompanied by molecular mechanics optimization
suggested that several crucial active site contacts were too short, the optimal distances corresponding to the minimum ab
initio interaction energy were also evaluated. Despite the deficiencies of force field-optimized enzyme-inhibitor structures,
satisfactory agreement with experimental inhibitory activity was obtained for the electrostatic interaction energy, suggesting
its possible application in the binding affinity prediction.
Figure The comparison of an arrangement of inhibitors within uPA active. Amino acid residues form S1 pocket that binds the variable
part of inhibitor molecules |
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Keywords: | Urokinase uPA inhibitor Docking FlexX Interaction energy Electrostatic interactions |
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