Application of a post-docking procedure based on MM-PBSA and MM-GBSA on single and multiple protein conformations

Sgobba, Miriam; Caporuscio, Fabiana; Anighoro, Andrew; Portioli, Corinne; Rastelli, Giulio

doi:10.1016/j.ejmech.2012.10.024

Cited by 78 publications

(66 citation statements)

References 40 publications

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“…BEAR has been extensively validated and used in prospective and retrospective drug discovery applications. By integrating the structural refinement of the docked poses with molecular dynamics and a more accurate ranking of potential ligands with MM-PBSA, BEAR proved to be able to significantly enrich ranked lists with biologically active compounds [18][19][20] and to discover active hits in previous virtual screening campaigns. 21 Before database screening, the docking protocol was tested for its ability to reproduce the crystallographic orientation of ANS.…”

Section: Resultsmentioning

confidence: 99%

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Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2

et al. 2014

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Section: Resultsmentioning

confidence: 99%

“…[18][19][20][21] Postdocking was performed on the top fraction of the ranked database obtained by applying an AutoDock energy score cut-off of −11 kcal/mol (~27 000 compounds, corresponding to ~5% of the initially docked database). The best AutoDock score was −15.6 kcal/mol.…”

Section: Post-docking With Bearmentioning

confidence: 99%

Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2

et al. 2014

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“…16 Sgobba and colleagues reported an assessment study of MM/GBSA and MM/ PBSA on six drug targets, and they found that MM/PBSA and MM/GBSA could give higher enrichment factors than the docking scoring functions but rescoring based on multiple protein conformations was not necessary for most cases. 17 Zhang et al have done a comprehensive study on the DUD dataset by using MM/GBSA, and summarized that using the top-5 originally scored docking poses for the MM/GBSA rescoring may be a good balance between computational burden and prediction accuracy. 18 However, we will show below that the influence of using the best scored docking pose or the best of the top-3 docking poses is not significant when a higher interior dielectric constant (i.e.…”

Section: Introductionmentioning

confidence: 99%

Assessing the performance of MM/PBSA and MM/GBSA methods. 5. Improved docking performance using high solute dielectric constant MM/GBSA and MM/PBSA rescoring

Sun

Shen

et al. 2014

Phys. Chem. Chem. Phys.

459

303

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With the rapid development of computational techniques and hardware, more rigorous and precise theoretical models have been used to predict the binding affinities of a large number of small molecules to biomolecules. By employing continuum solvation models, the MM/GBSA and MM/PBSA methodologies achieve a good balance between low computational cost and reasonable prediction accuracy. In this study, we have thoroughly investigated the effects of interior dielectric constant, molecular dynamics (MD) simulations, and the number of top-scored docking poses on the performance of the MM/GBSA and MM/PBSA rescoring of docking poses for three tyrosine kinases, including ABL, ALK, and BRAF. Overall, the MM/PBSA and MM/GBSA rescoring achieved comparative accuracies based on a relatively higher solute (or interior) dielectric constant (i.e. ε = 2, or 4), and could markedly improve the 'screening power' and 'ranking power' given by Autodock. Moreover, with a relatively higher solute dielectric constant, the MM/PBSA or MM/GBSA rescoring based on the best scored docking poses and the multiple top-scored docking poses gave similar predictions, implying that much computational cost can be saved by considering the best scored docking poses only. Besides, compared with the rescoring based on the minimized structures, the rescoring based on the MD simulations might not be completely necessary due to its negligible impact on the docking performance. Considering the much higher computational demand of MM/PBSA, MM/GBSA with a high solute dielectric constant (ε = 2 or 4) is recommended for the virtual screening of tyrosine kinases.

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“…ensemble docking) might further improve the enrichment of ligands by indirectly taking structural flexibility of the target into account [40][41][42][43][44]. GPCRs, which transition through a spectrum of active or inactive conformations, are a paramount case of target flexibility.…”

Section: Multiple Receptor Conformationsmentioning

confidence: 99%

Binding mode similarity measures for ranking of docking poses: a case study on the adenosine A2A receptor

Anighoro

Bajorath

2016

J Comput Aided Mol Des

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We report an investigation designed to explore alternative approaches for ranking of docking poses in the search for antagonists of the adenosine A2A receptor, an attractive target for structure-based virtual screening. Calculation of 3D similarity of docking poses to crystallographic ligand(s) as well as similarity of receptor-ligand interaction patterns was consistently superior to conventional scoring functions for prioritizing antagonists over decoys. Moreover, the use of crystallographic antagonists and agonists, a core fragment of an antagonist, and a model of an agonist placed into the binding site of an antagonist-bound form of the receptor resulted in a significant early enrichment of antagonists in compound rankings. Taken together, these findings showed that the use of binding modes of agonists and/or antagonists, even if they were only approximate, for similarity assessment of docking poses or comparison of interaction patterns increased the odds of identifying new active compounds over conventional scoring.

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Application of a post-docking procedure based on MM-PBSA and MM-GBSA on single and multiple protein conformations

Cited by 78 publications

References 40 publications

Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2

Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2

Assessing the performance of MM/PBSA and MM/GBSA methods. 5. Improved docking performance using high solute dielectric constant MM/GBSA and MM/PBSA rescoring

Binding mode similarity measures for ranking of docking poses: a case study on the adenosine A2A receptor

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