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Predicting binding energies of CDK6 inhibitors in the hit-to-lead process

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Abstract

The main challenge for the “hit-to-lead” stage in the drug discovery process relies on the accuracy of existing docking methods. In fact, accuracy of docking methods depends not only on the scoring function used to rank the poses but also on the ability of the docking method to reproduce the experimental binding mode. At this purpose, the performance of different approximations to properly dock and score compounds with known activity in a narrow range of IC50 values was analyzed. A set of five ATP-competitive CDK6 inhibitors and three receptor conformations for CDK6 were considered for analysis, and three methodologies were used and analyzed in order to include different degrees of receptor flexibility. Thus, a completely rigid receptor is considered when using Glide, while the so-called Induced Fit Docking Protocol accounts for receptor sidechain rearrangements. Finally, force field calculations were also performed in order to consider a completely flexible receptor.

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Acknowledgments

The Spanish Ministry of Science and Technology supported this work through project CTQ2006-06588/BQU. This work was also supported in part by the Generalitat de Catalunya through project 2009SGR1308. We are also grateful to the Departament d’Universitat, Recerca i Societat de la informació de la Generalitat de Catalunya i del Fons Social Europeu.

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Authors and Affiliations

  1. Department de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Martí i Franqués 1, 08028, Barcelona, Spain

    Laura Delgado-Soler, Javier Ariñez-Soriano & Jaime Rubio-Martinez

  2. Departmento de Química Física y Analítica, Universidad de Jaén, Campus Las Lagunillas s/n, 23071, Jaén, Spain

    José M. Granadino-Roldán

Authors
  1. Laura Delgado-Soler
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  2. Javier Ariñez-Soriano
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  3. José M. Granadino-Roldán
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  4. Jaime Rubio-Martinez
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Corresponding author

Correspondence to Jaime Rubio-Martinez.

Additional information

Published as part of the special issue celebrating theoretical and computational chemistry in Spain.

Electronic supplementary material

Table S-1 and S-2 containing detailed information about docking protocols. Table S-3 with the mean values of the three complexes for each MMPB/GBSA term and partial summation.

Supplementary material 1 (DOC 60 kb)

Supplementary material 2 (DOC 60 kb)

Supplementary material 3 (DOC 70 kb)

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Delgado-Soler, L., Ariñez-Soriano, J., Granadino-Roldán, J.M. et al. Predicting binding energies of CDK6 inhibitors in the hit-to-lead process. Theor Chem Acc 128, 807–823 (2011). https://doi.org/10.1007/s00214-010-0857-9

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  • DOI: https://doi.org/10.1007/s00214-010-0857-9

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