Abstract
Protein receptor conformations, obtained from molecular dynamics (MD) simulations, have become a promising treatment of its explicit flexibility in molecular docking experiments applied to drug discovery and development. However, incorporating the entire ensemble of MD conformations in docking experiments to screen large candidate compound libraries is currently an unfeasible task. Clustering algorithms have been widely used as a means to reduce such ensembles to a manageable size. Most studies investigate different algorithms using pairwise Root-Mean Square Deviation (RMSD) values for all, or part of the MD conformations. Nevertheless, the RMSD only may not be the most appropriate gauge to cluster conformations when the target receptor has a plastic active site, since they are influenced by changes that occur on other parts of the structure. Hence, we have applied two partitioning methods (k-means and k-medoids) and four agglomerative hierarchical methods (Complete linkage, Ward’s, Unweighted Pair Group Method and Weighted Pair Group Method) to analyze and compare the quality of partitions between a data set composed of properties from an enzyme receptor substrate-binding cavity and two data sets created using different RMSD approaches. Ensembles of representative MD conformations were generated by selecting a medoid of each group from all partitions analyzed. We investigated the performance of our new method for evaluating binding conformation of drug candidates to the InhA enzyme, which were performed by cross-docking experiments between a 20 ns MD trajectory and 20 different ligands. Statistical analyses showed that the novel ensemble, which is represented by only 0.48% of the MD conformations, was able to reproduce 75% of all dynamic behaviors within the binding cavity for the docking experiments performed. Moreover, this new approach not only outperforms the other two RMSD-clustering solutions, but it also shows to be a promising strategy to distill biologically relevant information from MD trajectories, especially for docking purposes.
Highlights
Molecular dynamics (MD) simulation and the insights it offers into protein motion is a powerful technique for understanding the structure and function of biological macromolecules in rational drug discovery [1, 2]
We identify ensembles of reduced and representative MD conformations from the best clustering solutions based on measures of dispersions of estimated Free Energy of Binding (FEB) values by docking experiments performed on AutoDock4 [23]
The work we present here analyzes and combines clustering partitions using three different data sets in order to reduce the structural redundancy in a 20 ns MD trajectory of a target protein receptor
Summary
Molecular dynamics (MD) simulation and the insights it offers into protein motion is a powerful technique for understanding the structure and function of biological macromolecules in rational drug discovery [1, 2]. A typical MD simulation may generate above of 104 conformations or snapshots to explore the conformational space of the protein concerned by individual particle motions as a function of time [1] This approach is time-consuming, it provides improved accuracy in the molecular docking process and opens new opportunities for the discovery of novel potential drugs [3]. The high computational cost involved in using FFR models to perform practical virtual screening in such ligand databases may make it unfeasible. For this reason, new and promising approaches to reduce the dimensionality of FFR models systematically—without losing critical structural information—should be investigated and applied [9]
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