2016
DOI: 10.1002/chem.201600993
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Exploiting Free‐Energy Minima to Design Novel EphA2 Protein–Protein Antagonists: From Simulation to Experiment and Return

Abstract: The free-energy surface (FES) of protein-ligand binding contains information useful for drug design. Here we show how to exploit a free-energy minimum of a protein-ligand complex identified by metadynamics simulations to design a new EphA2 antagonist with improved inhibitory potency.

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Cited by 16 publications
(24 citation statements)
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“…Molecular modeling investigations performed with classical force fields have identified a likely binding mode for these inhibitors consistent with available structure–activity relationship (SAR) data, i.e., proposing a reasonable role for the terminal carboxylic group and the amino acid side-chain of the inhibitors during their docking within EphA2 [ 13 , 14 ]. However, attempts to build quantitative models correlating experimental activities to docking energies led to modest results [ 13 ], suggesting that classical methods may not be able to properly describe accommodation of amino acid conjugates of LCA within EphA2 ligand binding domain (LBD).…”
Section: Introductionmentioning
confidence: 86%
See 1 more Smart Citation
“…Molecular modeling investigations performed with classical force fields have identified a likely binding mode for these inhibitors consistent with available structure–activity relationship (SAR) data, i.e., proposing a reasonable role for the terminal carboxylic group and the amino acid side-chain of the inhibitors during their docking within EphA2 [ 13 , 14 ]. However, attempts to build quantitative models correlating experimental activities to docking energies led to modest results [ 13 ], suggesting that classical methods may not be able to properly describe accommodation of amino acid conjugates of LCA within EphA2 ligand binding domain (LBD).…”
Section: Introductionmentioning
confidence: 86%
“…The most promising class is represented by lithocholic acid (LCA) and its -amino acid conjugates [ 7 , 13 ]. It has been demonstrated by surface plasmon resonance (SPR) analysis that this class of compounds prevents ephrin-A1 binding to EphA2 by targeting a conserved region of the ligand-binding domain of EphA2 [ 14 , 15 ].…”
Section: Introductionmentioning
confidence: 99%
“…In this respect, much has achieved in terms of free‐energy perturbation (FEP) calculations . We are confident that efficient and easy‐to‐prepare protocols and set‐ups for methods like steered‐MD and metadynamics will soon undergo similar improvements for prospective drug design . This will further open up these methods to computational medicinal chemistry.…”
Section: Improved Sampling Of Configuration Space Through Dynamic Docmentioning
confidence: 99%
“…From the first application of metadynamics to small molecule binding studies, we have now seen prospective applications of this method to estimate the binding affinity of compounds. These compounds have then been prioritized accordingly for synthesis and experimental tests during drug discovery projects …”
Section: Path‐based Versus Alchemical Transformations In Dynamic Dockingmentioning
confidence: 99%
“…Metadynamics (MTD) is an enhanced sampling method that increases the probability of reaching high free-energy states by adding a Gaussian bias potential to the Hamiltonian of a state 6,7 . The MTD method has been used to analyze reaction pathways [8][9][10][11][12][13][14][15] , the conformations of additives at crystal surfaces [16][17][18][19] , crystal structures [20][21][22][23][24][25] , crystal nucleation [26][27][28][29][30][31][32][33] , drug design [34][35][36][37][38] , and the transport mechanism of an ion in a sub-nanopore 39 . The MTD method affords a free-energy landscape in a space of collective variables (CVs) for a system of interest.…”
mentioning
confidence: 99%