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Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand.

ABSTRACT: RosettaLigand has been successfully used to predict binding poses in protein-small molecule complexes. However, the RosettaLigand docking protocol is comparatively slow in identifying an initial starting pose for the small molecule (ligand) making it unfeasible for use in virtual High Throughput Screening (vHTS). To overcome this limitation, we developed a new sampling approach for placing the ligand in the protein binding site during the initial 'low-resolution' docking step. It combines the translational and rotational adjustments to the ligand pose in a single transformation step. The new algorithm is both more accurate and more time-efficient. The docking success rate is improved by 10-15% in a benchmark set of 43 protein/ligand complexes, reducing the number of models that typically need to be generated from 1000 to 150. The average time to generate a model is reduced from 50 seconds to 10 seconds. As a result we observe an effective 30-fold speed increase, making RosettaLigand appropriate for docking medium sized ligand libraries. We demonstrate that this improved initial placement of the ligand is critical for successful prediction of an accurate binding position in the 'high-resolution' full atom refinement step.

SUBMITTER: DeLuca S

PROVIDER: S-EPMC4514752 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand.

DeLuca Samuel S Khar Karen K Meiler Jens J

PloS one 20150724 7

RosettaLigand has been successfully used to predict binding poses in protein-small molecule complexes. However, the RosettaLigand docking protocol is comparatively slow in identifying an initial starting pose for the small molecule (ligand) making it unfeasible for use in virtual High Throughput Screening (vHTS). To overcome this limitation, we developed a new sampling approach for placing the ligand in the protein binding site during the initial 'low-resolution' docking step. It combines the tr ...[more]

PMID: 26207742

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Project description:BACKGROUND:Protein-ligand docking has emerged as a particularly important tool in drug design and development, and flexible ligand docking is a widely used method for docking simulations. Many docking software packages can simulate flexible ligand docking, and among them, Autodock is widely used. Focusing on the search algorithm used in Autodock, many new optimization approaches have been proposed over the last few decades. However, despite the large number of alternatives, we are still lacking a search method with high robustness and high performance. RESULTS:In this paper, in conjunction with the popular Autodock software, a novel hybrid version of the random drift particle swarm optimization (RDPSO) algorithm, called diversity-guided Lamarckian RDPSO (DGLRDPSO), is proposed to further enhance the performance and robustness of flexible ligand docking. In this algorithm, a novel two-phase diversity control (2PDC) strategy and an efficient local search strategy are used to improve the search ability and robustness of the RDPSO algorithm. By using the PDBbind coreset v.2016 and 24 complexes with apo-structures, the DGLRDPSO algorithm is compared with the Lamarckian genetic algorithm (LGA), Lamarckian particle swarm optimization (LPSO) and Lamarckian random drift particle swarm optimization (LRDPSO). The experimental results show that the 2PDC strategy is able to enhance the robustness and search performance of the proposed algorithm; for test cases with different numbers of torsions, the DGLRDPSO outperforms the LGA and LPSO in finding both low-energy and small-RMSD docking conformations with high robustness in most cases. CONCLUSION:The DGLRDPSO algorithm has good search performance and a high possibility of finding a conformation with both a low binding free energy and a small RMSD. Among all the tested algorithms, DGLRDPSO has the best robustness in solving both holo- and apo-structure docking problems with different numbers of torsions, which indicates that the proposed algorithm is a reliable choice for the flexible ligand docking in Autodock software.

Project description:BACKGROUND:In the rational drug design process, an ensemble of conformations obtained from a molecular dynamics simulation plays a crucial role in docking experiments. Some studies have found that Fully-Flexible Receptor (FFR) models predict realistic binding energy accurately and improve scoring to enhance selectiveness. At the same time, methods have been proposed to reduce the high computational costs involved in considering the explicit flexibility of proteins in receptor-ligand docking. This study introduces a novel method to optimize ensemble docking-based experiments by reducing the size of an InhA FFR model at docking runtime and scaling docking workflow invocations on cloud virtual machines. RESULTS:First, in order to find the most affordable cost-benefit pool of virtual machines, we evaluated the performance of the docking workflow invocations in different configurations of Azure instances. Second, we validated the gains obtained by the proposed method based on the quality of the Reduced Fully-Flexible Receptor (RFFR) models produced using AutoDock4.2. The analyses show that the proposed method reduced the model size by approximately 50% while covering at least 86% of the best docking results from the 74 ligands tested. Third, we tested our novel method using AutoDock Vina, a different docking software, and showed the positive accuracy achieved in the resulting RFFR models. Finally, our results demonstrated that the method proposed optimized ensemble docking experiments and is applicable to different docking software. In addition, it detected new binding modes, which would be unreachable if employing only the rigid structure used to generate the InhA FFR model. CONCLUSIONS:Our results showed that the selective method is a valuable strategy for optimizing ensemble docking-based experiments using different docking software. The RFFR models produced by discarding non-promising snapshots from the original model are accurately shaped for a larger number of ligands, and the elapsed time spent in the ensemble docking experiments are considerably reduced.

Dataset Information

Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand.

Publications

Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand.

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