Development and validation of a modular, extensible docking program: DOCK 5
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We report on the development and validation of a new version of DOCK. The algorithm has been rewritten in a modular format, which allows for easy implementation of new scoring functions, sampling methods and analysis tools. We validated the sampling algorithm with a test set of 114 protein–ligand complexes. Using an optimized parameter set, we are able to reproduce the crystal ligand pose to within 2 Å of the crystal structure for 79% of the test cases using our rigid ligand docking algorithm with an average run time of 1 min per complex and for 72% of the test cases using our flexible ligand docking algorithm with an average run time of 5 min per complex. Finally, we perform an analysis of the docking failures in the test set and determine that the sampling algorithm is generally sufficient for the binding pose prediction problem for up to 7 rotatable bonds; i.e. 99% of the rigid ligand docking cases and 95% of the flexible ligand docking cases are sampled successfully. We point out that success rates could be improved through more advanced modeling of the receptor prior to docking and through improvement of the force field parameters, particularly for structures containing metal-based cofactors.
KeywordsAutomated docking Scoring functions Structure-based drug design Flexible docking Binding mode prediction Incremental construction Validation
Gratitude is expressed to Dr. Bentley Strockbine and Sudipto Mukherjee for computational assistance with MPI calculations. Demetri Moustakas, Natasja Brooijmans, P. Therese Lang and Irwin D. Kuntz would like to thank the NIH grant GM 56531 (Paul Ortiz de Montellano, PI) for support. P. Therese Lang would also like to thank the Burroughs Welcome Foundation and the American Foundation for Pharmaceutical Education for additional support. The authors would like to thank Scott Brozell, Mathew Jacobson, and Brian Shoichet and members of his group for helpful conversations.
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