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Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge

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Abstract

SAMPL3 fragment based virtual screening challenge provides a valuable opportunity for researchers to test their programs, methods and screening protocols in a blind testing environment. We participated in SAMPL3 challenge and evaluated our virtual fragment screening protocol, which involves RosettaLigand as the core component by screening a 500 fragments Maybridge library against bovine pancreatic trypsin. Our study reaffirmed that the real test for any virtual screening approach would be in a blind testing environment. The analyses presented in this paper also showed that virtual screening performance can be improved, if a set of known active compounds is available and parameters and methods that yield better enrichment are selected. Our study also highlighted that to achieve accurate orientation and conformation of ligands within a binding site, selecting an appropriate method to calculate partial charges is important. Another finding is that using multiple receptor ensembles in docking does not always yield better enrichment than individual receptors. On the basis of our results and retrospective analyses from SAMPL3 fragment screening challenge we anticipate that chances of success in a fragment screening process could be increased significantly with careful selection of receptor structures, protein flexibility, sufficient conformational sampling within binding pocket and accurate assignment of ligand and protein partial charges.

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Acknowledgments

We thank RIKEN Integrated Cluster of Clusters (RICC) at RIKEN for the supercomputing resources used for the study. We are grateful to Dr. Tom Peat for sharing the crystal structures of trypsin bound with active fragments prior to publication. We thank members of our lab for help and discussions. We acknowledge the Initiative Research Unit program from RIKEN, Japan for funding.

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  1. Zhang Initiative Research Unit, Advanced Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan

    Ashutosh Kumar & Kam Y. J. Zhang

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Correspondence to Kam Y. J. Zhang.

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Kumar, A., Zhang, K.Y.J. Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge. J Comput Aided Mol Des 26, 603–616 (2012). https://doi.org/10.1007/s10822-011-9523-0

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