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The performance of ensemble-based free energy protocols in computing binding affinities to ROS1 kinase.
Wan, Shunzhou; Bhati, Agastya P; Wright, David W; Wade, Alexander D; Tresadern, Gary; van Vlijmen, Herman; Coveney, Peter V.
Afiliación
  • Wan S; Department of Chemistry, Centre for Computational Science, University College London, London, UK.
  • Bhati AP; Department of Chemistry, Centre for Computational Science, University College London, London, UK.
  • Wright DW; Department of Chemistry, Centre for Computational Science, University College London, London, UK.
  • Wade AD; Department of Chemistry, Centre for Computational Science, University College London, London, UK.
  • Tresadern G; Computational Chemistry, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
  • van Vlijmen H; Computational Chemistry, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
  • Coveney PV; Department of Chemistry, Centre for Computational Science, University College London, London, UK. p.v.coveney@ucl.ac.uk.
Sci Rep ; 12(1): 10433, 2022 06 21.
Article en En | MEDLINE | ID: mdl-35729177
Optimization of binding affinities for compounds to their target protein is a primary objective in drug discovery. Herein we report on a collaborative study that evaluates a set of compounds binding to ROS1 kinase. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling) protocols to rank the binding free energies. The predicted binding free energies from ESMACS simulations show good correlations with experimental data for subsets of the compounds. Consistent binding free energy differences are generated for TIES and ESMACS. Although an unexplained overestimation exists, we obtain excellent statistical rankings across the set of compounds from the TIES protocol, with a Pearson correlation coefficient of 0.90 between calculated and experimental activities.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Proteínas Proto-Oncogénicas Idioma: En Revista: Sci Rep Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Proteínas Proto-Oncogénicas Idioma: En Revista: Sci Rep Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido