Hierarchical Docking of Databases of Multiple Ligand Conformations

Abstract

Ligand flexibility is an important problem in molecular docking and virtual screening. To address this challenge, we investigate a hierarchical pre-organization of multiple conformations of small molecules. Such organization of pre-calculated conformations removes the exploration of ligand conformational space from the docking calculation and allows for concise representation of what can be thousands of conformations. The hierarchy also recognizes and prunes incompatible conformations early in the calculation, eliminating redundant calculations of fit. We investigate the method by docking the MDL Drug Data Report (MDDR), an annotated database of 100,000 molecules, into apo and holo forms of seven unrelated targets. This annotated database allows us to track the ranking of tens to hundreds of annotated ligands in each of the docking systems. The binding sites and database are prepared in an automated fashion in an attempt to remove some human bias from the calculations. Many thousands of explicit and implicit ligand conformations may be docked in calculations not much longer than required for single conformer docking. As long as internal energies are not considered, recombination with the hierarchy is additive as the number of degrees of freedom is increased. Molecules with even millions of conformations can be docked in a few minutes on a single desktop computer.

Structure-based Discovery of Antagonists of Nuclear Receptor LRH-1

“…Molecular Docking Calculations-DOCK3.6 (37)(38)(39)(40) was used to screen a library of commercially available compounds against a model of LRH-1 LBD in a transcriptionally inactive conformation. The flexible ligand sampling algorithm in DOCK3.6 superimposes atoms of the docked molecule onto spheres matching a defined binding site; these spheres represent favorable positions for individual ligand atoms (39,40).…”

“…The flexible ligand sampling algorithm in DOCK3.6 superimposes atoms of the docked molecule onto spheres matching a defined binding site; these spheres represent favorable positions for individual ligand atoms (39,40). Fifty matching spheres mimicking the inside of the receptor ligand-binding pocket (LBP) were used for the molecular docking calculations.…”

Benchmarking Sets for Molecular Docking

“…AMSOL and Omega results were combined into a single "flexibase" format file using our program Mol2db. 33 All new parameter files used in this process (rules.txt, tautomer_list, ionizer.ini, and torlib.txt) are available in the Supplementary Material.…”

“…33,47,56 The sampling of ligand orientations in DOCK3.5.54 can be varied according to several user-defined parameters, which we set to the same values for all 40 systems, as follows. The bin size for both receptor and ligand were set to 0.4 Å and the overlap bin size was set to 0.3 Å.…”

High Selectivity of the γ-Aminobutyric Acid Transporter 2 (GAT-2, SLC6A13) Revealed by Structure-based Approach

“…All of the docking calculations were performed with DOCK 3.5.54 (37,38). The docking poses of database molecules were ranked by DOCK score consisting of van der Waals, Poisson-Boltzmann electrostatic, and ligand desolvation penalty terms.…”