Flexible ligand docking using conformational ensembles

Abstract

Molecular docking algorithms suggest possible structures for molecular complexes. They are used to model biological function and to discover potential ligands. A present challenge for docking algorithms is the treatment of molecular flexibility. Here, the rigid body program, DOCK, is modified to allow it to rapidly fit multiple conformations of ligands. Conformations of a given molecule are pre-calculated in the same frame of reference, so that each conformer shares a common rigid fragment with all other conformations. The ligand conformers are then docked together, as an ensemble, into a receptor binding site. This takes advantage of the redundancy present in differing conformers of the same molecule. The algorithm was tested using three organic ligand protein systems and two protein-protein systems. Both the bound and unbound conformations of the receptors were used. The ligand ensemble method found conformations that resembled those determined in X-ray crystal structures (RMS values typically less than 1.5 A). To test the method's usefulness for inhibitor discovery, multi-compound and multi-conformer databases were screened for compounds known to bind to dihydrofolate reductase and compounds known to bind to thymidylate synthase. In both cases, known inhibitors and substrates were identified in conformations resembling those observed experimentally. The ligand ensemble method was 100-fold faster than docking a single conformation at a time and was able to screen a database of over 34 million conformations from 117,000 molecules in one to four CPU days on a workstation.

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.…”

Structure-Based Drug Design: Docking and Scoring

“…To this end, 10 different enzyme-binding sites, represented by their holo, apo, and model structures, were investigated. The MDDR (MDL Drug Data Report) database of 95 000 small molecules containing at least 35 ligands for each of the 10 systems was docked against all 30 structures using the DOCK program [61,62]. The ability of each structure to enrich the known ligands for that enzyme over random selection was evaluated.…”

Synthesis and Structure Activity Relationship of Some Indole Derivatives as Potential Anti-inflammatory Agents

“…68 A molecular docking study had been done using both MOE 2013.08 71 and Leadit 2.1.2 software. 72,73 Possible binding modes of the active compounds inside the active site of COX-2 were estimated. Indomethacin and ibuprofen were also docked.…”