Molecular dynamics simulations studies and free energy analysis on inhibitors of MDM2–p53 interaction

Niu, Rui-Juan; Zheng, Qing‐Chuan; Zhang, Ji-Long; Zhang, Hongxing

doi:10.1016/j.jmgm.2013.10.005

Cited by 17 publications

(8 citation statements)

References 39 publications

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“…The RMSF graph (Fig. 4b) shows clearly that the terminal regions of MDM2 undergo significant conformational changes of much higher fluctuation levels than those obtained in all-atom MD simulations2531323334.…”

Section: Resultsmentioning

confidence: 87%

“…To our best knowledge, investigations of MDM2 flexibility during p53 binding have been limited so far either by ignoring the entire lid fragment in the simulation system and/or too short simulation timescales: of a nanosecond2531323334 or a microsecond26 scale. A very recent computational study, constructing Markov State Models from many independent trajectories of apo-MDM254, suggests that even microsecond MD simulations of apo-MDM2 are not sufficient to adequately sample the conformational space of the flexible lid in the unbound receptor.…”

Section: Discussionmentioning

confidence: 99%

“…( b ) RMSF (root-mean square fluctuation) averaged over the trajectory from the CABS-dock simulation (blue line). The grey rectangle shows the area investigated so far with all-atom MD (reported in refs 25,31, 32, 33, 34). The rectangle borders show the maximal RMSF value obtained and the largest MDM2 fragment included in these simulations.…”

Section: Figurementioning

confidence: 99%

“…To our best knowledge, the previous simulations of this complex were limited to too short simulation timescales (see Discussion) and/or shortened variants of MDM2 that excluded entire or significant portions of the highly flexible regions252631323334. In the modeling procedures, we have not used any information on either the docking site or the peptide structure in the complex.…”

mentioning

confidence: 99%

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Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

Ciemny

Dębiński

Paczkowska

et al. 2016

Sci Rep

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Protein-peptide interactions are often associated with large-scale conformational changes that are difficult to study either by classical molecular modeling or by experiment. Recently, we have developed the CABS-dock method for flexible protein-peptide docking that enables large-scale rearrangements of the protein chain. In this study, we use CABS-dock to investigate the binding of the p53-MDM2 complex, an element of the cell cycle regulation system crucial for anti-cancer drug design. Experimental data suggest that p53-MDM2 binding is affected by significant rearrangements of a lid region - the N-terminal highly flexible MDM2 fragment; however, the details are not clear. The large size of the highly flexible MDM2 fragments makes p53-MDM2 intractable for exhaustive binding dynamics studies using atomistic models. We performed extensive dynamics simulations using the CABS-dock method, including large-scale structural rearrangements of MDM2 flexible regions. Without a priori knowledge of the p53 peptide structure or its binding site, we obtained near-native models of the p53-MDM2 complex. The simulation results match well the experimental data and provide new insights into the possible role of the lid fragment in p53 binding. The presented case study demonstrates that CABS-dock methodology opens up new opportunities for protein-peptide docking with large-scale changes of the protein receptor structure.

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Section: Resultsmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

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Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

Ciemny

Dębiński

Paczkowska

et al. 2016

Sci Rep

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show abstract

“…For these reasons, MD represents a powerful tool to explore the small molecule–MDM2 interactions providing clues to design new inhibitors. The p53–MDM2 complex has been investigated to explore the binding interface or the effect of mutated key residues in the human p53–MDM2 complex …”

Section: Screening Approaches To Search For Inhibitors Of the P53–mdmmentioning

confidence: 99%

Medicinal Chemistry Strategies to Disrupt the p53–MDM2/MDMX Interaction

Lemos

Leão

Soares

et al. 2016

Medicinal Research Reviews

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The growth inhibitory activity of p53 tumor suppressor is tightly regulated by interaction with two negative regulatory proteins, murine double minute 2 (MDM2) and X (MDMX), which are overexpressed in about half of all human tumors. The elucidation of crystallographic structures of MDM2/MDMX complexes with p53 has been pivotal for the identification of several classes of inhibitors of the p53-MDM2/MDMX interaction. The present review provides in silico strategies and screening approaches used in drug discovery as well as an overview of the most relevant classes of small-molecule inhibitors of the p53-MDM2/MDMX interaction, their progress in pipeline, and highlights particularities of each class of inhibitors. Most of the progress made with high-throughput screening has led to the development of inhibitors belonging to the cis-imidazoline, piperidinone, and spiro-oxindole series. However, novel potent and selective classes of inhibitors of the p53-MDM2 interaction with promising antitumor activity are emerging. Even with the discovery of the 3D structure of complex p53-MDMX, only two small molecules were reported as selective p53-MDMX antagonists, WK298 and SJ-172550. Dual inhibition of the p53-MDM2/MDMX interaction has shown to be an alternative approach since it results in full activation of the p53-dependent pathway. The knowledge of structural requirements crucial to the development of small-molecule inhibitors of the p53-MDMs interactions has enabled the identification of novel antitumor agents with improved in vivo efficacy.

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Tailoring Proteins to Re-Evolve Nature: A Short Review

Jimenez-Rosales

Flores-Merino

2018

Mol Biotechnol

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Molecular dynamics simulations studies and free energy analysis on inhibitors of MDM2–p53 interaction

Cited by 17 publications

References 39 publications

Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

Medicinal Chemistry Strategies to Disrupt the p53–MDM2/MDMX Interaction

Tailoring Proteins to Re-Evolve Nature: A Short Review

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