Combining Pharmacophore Search, Automated Docking, and Molecular Dynamics Simulations as a Novel Strategy for Flexible Docking. Proof of Concept:  Docking of Arginine−Glycine−Aspartic Acid-like Compounds into the α_vβ₃ Binding Site

Abstract

A novel and highly efficient flexible docking approach is presented where the conformations (internal degrees of freedom) and orientations (external degrees of freedom) of the ligands are successively considered. This hybrid method takes advantage of the synergistic effects of structure-based and ligand-based drug design techniques. Preliminary antagonist-derived pharmacophore determination provides the postulated bioactive conformation. Subsequent docking of this pharmacophore to the receptor crystal structure results in a postulated pharmacophore/receptor binding mode. Pharmacophore-oriented docking of antagonists is subsequently achieved by matching ligand interacting groups with pharmacophore points. Molecular dynamics in water refines the proposed complexes. To validate the method, arginine-glycine-aspartic acid (RGD) containing peptides, pseudopeptides, and RGD-like antagonists were docked to the crystal structure of alphavbeta3 holoprotein and apoprotein. The proposed directed docking was found to be more accurate, faster, and less biased with respect to the protein structure (holo and apoprotein) than DOCK, Autodock, and FlexX docking methods. The successful docking of an antagonist recently cocrystallized with the receptor to both apo and holoprotein is particularly appealing. The results summarized in this report illustrated the efficiency of our light CoMFA/rigid body docking hybrid method.

αvβ3 Integrin-Targeting Arg-Gly-Asp (RGD) Peptidomimetics Containing Oligoethylene Glycol (OEG) Spacers

“…Our molecules compare with the cyclic peptide cilengitide for which the bioactive conformation is known from X-ray data. 72 Their extended conformations are in good agreement with the three-point pharmacophore 73 Because of the size of the systems, the graftable peptidomimetics 8a and 8b (see structures in Table 4) were studied in MINI1 basis. Two accessible extended conformations were found, referred to as Exten 1 (reference) and Exten 2 ( Figure 4).…”

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

“…Docking studies were performed using the Molecular Forecaster suite of docking software developed at and licensed by McGill University (Montreal, QC, Canada) (Moitessier et al, 2004) and its associated modules. Default settings were used unless otherwise noted.…”

MD-2-mediated Ionic Interactions between Lipid A and TLR4 Are Essential for Receptor Activation

“…Mouse TLR4 was omitted from initial docking because only MD-2, but not TLR4, has been demonstrated to bind LPS or its analogs directly (13). We used the AutoDock docking software, because this approach produces ligand⅐receptor complexes that closely resemble co-crystal structures (30). In a quality control experiment (supplemental Fig.…”