Abstract
<p class="ADMETabstracttext">Due to its crucial role in nucleotide metabolism, adenylate kinase deserves a special attention in screening of potential inhibitors. Herein, we report the assessment of the relative orientation of the ligand 2,4-thiazolidinedione to adenylate kinase crystallized in closed conformation. Protein-ligand docking was performed to estimate the binding energy and inhibition constant of 2,4-thiazolidinedione to the adenylate kinases’ active sites from different organisms. Our results revealed the best orientation of 2,4-thiazolidinedione is with Gram-positive and acid fast bacteria adenylate kinase – K<sub>i</sub> = 0.76±0.1 mM and binding energy -4.26±0.08 kcal/mol. Human adenylate kinases display unfavourable interactions, the binding affinity fluctuating among K<sub>i</sub>=0.84 mM and 8.8 mM (3.88±3.51); the energy binding -3.56±0.57. From the three human adenylate kinases analysed, only isoenzyme 2 shows a binding conformation similar to its counterpart from E. coli. Adenylate kinase - this small enzyme needed for survival of every organisms - interacts differently with 2,4-thiazolidinedione, this selectivity being the most important evidence of the present study.</p>
Highlights
Bacterial resistance to antibiotics is an evolving problem of medical practice [1,2]
Adenylate kinase (AK) from different sources were subjected to docking with 2,4-thiazolidinedione
This study demonstrated an effort to reveal interactions of AK of bacterial / human origin with 2,4thiazolidinedione
Summary
Bacterial resistance to antibiotics is an evolving problem of medical practice [1,2]. Discovery of new antibacterial agents and/or reevaluating of different targets are impetuously needed [3], [4]. These kinds of studies are usually constructed by comparison of well characterized pathogens. AK is, due to its universality and its flexibility, an attractive target for screening of new inhibitors. Thiazolidinediones (TZDs) derivates – synthetic agonists for the peroxisome proliferator-activating receptorgamma receptor – were demonstrated as potential inhibitors of S. pneumoniae out-growth [11]. As we are interested in inhibition of AK by thiazolidine derivates [12], the present study is focused on 2,4thiazolidinedione interaction with the active site of bacterial and human AKs
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