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Docking and scoring with ICM: the benchmarking results and strategies for improvement

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Abstract

Flexible docking and scoring using the internal coordinate mechanics software (ICM) was benchmarked for ligand binding mode prediction against the 85 co-crystal structures in the modified Astex data set. The ICM virtual ligand screening was tested against the 40 DUD target benchmarks and 11-target WOMBAT sets. The self-docking accuracy was evaluated for the top 1 and top 3 scoring poses at each ligand binding site with near native conformations below 2 Å RMSD found in 91 and 95% of the predictions, respectively. The virtual ligand screening using single rigid pocket conformations provided the median area under the ROC curves equal to 69.4 with 22.0% true positives recovered at 2% false positive rate. Significant improvements up to ROC AUC = 82.2 and ROC(2%) = 45.2 were achieved following our best practices for flexible pocket refinement and out-of-pocket binding rescore. The virtual screening can be further improved by considering multiple conformations of the target.

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Acknowledgments

M.A.C. Neves thanks Fundação para a Ciência e a Tecnologia (FCT), Portugal, for a Post Doctoral grant (SFRH/BPD/64216/2009). The authors thank Irina Kufareva, Manuel Rueda, Winston Chen, Chayan Acharya and Chris Edwards for useful discussions and comments. This work was supported by National Institutes of Health [grant numbers R01 GM071872, U01 GM094612 and U54 GM094618].

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Authors and Affiliations

  1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Marco A. C. Neves & Ruben Abagyan

  2. Lab. Química Farmacêutica, Centro de Neurociências, Faculdade de Farmácia, Universidade de Coimbra, Pólo das Ciências da Saúde, 3000-548, Coimbra, Portugal

    Marco A. C. Neves

  3. Molsoft L.L.C, 11199 Sorrento Valley Road, S209, San Diego, CA, 92121, USA

    Maxim Totrov & Ruben Abagyan

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  1. Marco A. C. Neves
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Correspondence to Ruben Abagyan.

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Neves, M.A.C., Totrov, M. & Abagyan, R. Docking and scoring with ICM: the benchmarking results and strategies for improvement. J Comput Aided Mol Des 26, 675–686 (2012). https://doi.org/10.1007/s10822-012-9547-0

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  • DOI: https://doi.org/10.1007/s10822-012-9547-0

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