A computational analysis of the binding model of MDM2 with inhibitors |
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Authors: | Guodong Hu Dunyou Wang Xinguo Liu Qinggang Zhang |
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Institution: | (1) College of Physics and Electronics, Shandong Normal University, 250014 Jinan, China;(2) Department of Physics, University of Texas at San Antonio, San Antonio, TX 78249, USA; |
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Abstract: | Abstract It is a new and promising strategy for anticancer drug design to block the MDM2-p53 interaction using a non-peptide small-molecule
inhibitor. We carry out molecular dynamics simulations to study the binding of a set of six non-peptide small-molecule inhibitors
with the MDM2. The relative binding free energies calculated using molecular mechanics Poisson–Boltzmann surface area method
produce a good correlation with experimentally determined results. The study shows that the van der Waals energies are the
largest component of the binding free energy for each complex, which indicates that the affinities of these inhibitors for
MDM2 are dominated by shape complementarity. The A-ligands and the B-ligands are the same except for the conformation of 2,2-dimethylbutane
group. The quantum mechanics and the binding free energies calculation also show the B-ligands are the more possible conformation
of ligands. Detailed binding free energies between inhibitors and individual protein residues are calculated to provide insights
into the inhibitor-protein binding model through interpretation of the structural and energetic results from the simulations.
The study shows that G1, G2 and G3 group mimic the Phe19, Trp23 and Leu26 residues in p53 and their interactions with MDM2,
but the binding model of G4 group differs from the original design strategy to mimic Leu22 residue in p53. |
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