FReDoWS: a method to automate molecular docking simulations with explicit receptor flexibility and snapshots selection

Karina S Machado,Evelyn K Schroeder,Elisângela Ml Cohen,Duncan D Ruiz,Osmar Norberto De Souza

doi:10.1186/1471-2164-12-s4-s6

Karina S Machado, Evelyn K Schroeder + Show 3 more

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https://doi.org/10.1186/1471-2164-12-s4-s6

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Abstract

BackgroundIn silico molecular docking is an essential step in modern drug discovery when driven by a well defined macromolecular target. Hence, the process is called structure-based or rational drug design (RDD). In the docking step of RDD the macromolecule or receptor is usually considered a rigid body. However, we know from biology that macromolecules such as enzymes and membrane receptors are inherently flexible. Accounting for this flexibility in molecular docking experiments is not trivial. One possibility, which we call a fully-flexible receptor model, is to use a molecular dynamics simulation trajectory of the receptor to simulate its explicit flexibility. To benefit from this concept, which has been known since 2000, it is essential to develop and improve new tools that enable molecular docking simulations of fully-flexible receptor models.ResultsWe have developed a Flexible-Receptor Docking Workflow System (FReDoWS) to automate molecular docking simulations using a fully-flexible receptor model. In addition, it includes a snapshot selection feature to facilitate acceleration the virtual screening of ligands for well defined disease targets. FReDoWS usefulness is demonstrated by investigating the docking of four different ligands to flexible models of Mycobacterium tuberculosis’ wild type InhA enzyme and mutants I21V and I16T. We find that all four ligands bind effectively to this receptor as expected from the literature on similar, but wet experiments.ConclusionsA work that would usually need the manual execution of many computer programs, and the manipulation of thousands of files, was efficiently and automatically performed by FReDoWS. Its friendly interface allows the user to change the docking and execution parameters. Besides, the snapshot selection feature allowed the acceleration of docking simulations. We expect FReDoWS to help us explore more of the role flexibility plays in receptor-ligand interactions. FReDoWS can be made available upon request to the authors.

Highlights

In silico molecular docking is an essential step in modern drug discovery when driven by a well defined macromolecular target
In Flexible-Receptor Docking Workflow System (FReDoWS), the Prepare macro subflow has two activities: (1) execution of Ptraj to transform the molecular dynamics (MD) trajectory files into the Protein Data Bank (PDB) [5] format used by almost all docking software [7,8,9], and (2) execution of a script to pick up snapshots separated by time intervals larger than or equal to the frequency with which snapshots are saved from the MD simulation
FReDoWS usefulness was demonstrated by the investigation of the docking of four different ligands to the Mycobacterium tuberculosis InhA enzyme

Summary

Introduction

In silico molecular docking is an essential step in modern drug discovery when driven by a well defined macromolecular target. In the RDD’s first step the structure of the target receptor (hereinafter receptor is used as synonymous of macromolecule and protein) provides a starting point for direct modeling activities During this step, the three-dimensional (3-D) structure of the receptor obtained, for example, from the Protein Data Bank (PDB) [5], is analyzed in order to identify probable binding sites. In the second step, based on such probable binding sites, a set of possible ligands (hereinafter ligand, inhibitor and small molecules have the same meaning) is selected. In the third step, the receptor-ligand interactions are evaluated by computer simulations using molecular docking software, of which AutoDock [7], DOCK [8], and FlexE [9] are just a few examples Throughout this step the ligands that had the best interaction score to the receptor are selected, bought or synthesized, and wet-experimentally tested. In the fourth step, based on the in vitro results, an inhibitor candidate is detected, or the process returns to the first step

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