The binding mechanism of a novel nicotinamide isostere inhibiting with TNKSs: a molecular dynamic simulation and binding free energy calculation.
Tankyrases (TNKSs), a member of human poly (ADP-ribose) polymerase (PARP) protein superfamily, plays a key role in regulation of cell proliferation. Among the representative proteins of the PARPs family, it is found that the inhibitors have high selectivity for Tankyrase1 (TNKS1). The specific binding modes are investigated between the TNKS1 protein and nicotinamide isostere (ISX) which functions as an inhibitor of TNKS1. The stabilities of ISX-TNKS1 and AVA939-TNKS1 complexes are estimated by molecular dynamics (MD) simulations and free energy calculations; a good agreement with experimental results is reached. On the basis of the calculated results of MD simulations, we found that the inhibitors influence the conformational flexibility of TNKS1 and the XAV939 binding drive the peptide Ile1228-Gly1229-Gly1230 to form a helical structure while the ISX binding drive the peptide to form a turn structure. Moreover, the formed important hydrogen bonds of Tyr1203 residue with XVA939 and WAT1551 with ISX enhance stabilities of the complexes, and the electrostatic interactions in XAV939-TNKS1 and van der Waals interactions in ISX-TNKS1 system are main driving forces for affinity. According to the results of the decomposition of binding free energy, it is obvious that the residues Try1224 and Lys1220 make the most favorable contributions to the binding in, respectively, ISX and XAV939 complexes. Taken together, the obtained results are useful for studying the binding mechanisms of TNKSs and inhibitors and for designing potent inhibitors.
a National Synchrotron Radiation Laboratory , University of Science and Technology of China , Hefei 230029 , P.R. China.|b College of Basic Medical Sciences of Anhui Medical University , Hefei 230024 , P.R. China.
Ting-Ting
TT
Feng
a National Synchrotron Radiation Laboratory , University of Science and Technology of China , Hefei 230029 , P.R. China.
Yan-Jun
YJ
Zhang
a National Synchrotron Radiation Laboratory , University of Science and Technology of China , Hefei 230029 , P.R. China.
H
H
Chen
c Department of Urology and Anhui Geriatric Institute , The First Affiliated Hospital of Anhui Medical University , Hefei 230025 , P.R. China.
Song
S
Fan
a National Synchrotron Radiation Laboratory , University of Science and Technology of China , Hefei 230029 , P.R. China.
Ju-Guang
JG
Han
D000465:Algorithms; D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009536:Niacinamide / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; C544261:XAV939; D009536:Niacinamide; D038501:Tankyrases
ISX; TNKS1; XAV939; binding mechanism; molecular dynamics simulation