David M. Ferguson, Fellow

Computer Modeling of Biomolecular Complexes and Ligand Recognition

  The structure, function, and dynamics of macromolecules and macromolecular interactions were studied using a variety of computational techniques by these researchers. These included molecular graphics, empirical force fields, ab initio calculations, molecular docking, and molecular dynamics simulations. The primary emphasis of this work focuses on the development and application of structural models of G protein-coupled receptors (GPCRs) to ligand design.

  In particular, the researchers were concerned with developing highly selective opioid ligands with modified pharmacological properties. A second area of emphasis was placed on studying the structure, dynamics, and thermodynamic stability of modified nucleic acid complexes for use in antisense drug development. Both projects required significant force field parameterization, ab initio model calculations, and long time-scale molecular dynamics simulations, as well as graphics visualizations with the long-term goal of modeling molecular recognition processes reliably and confidently for use in drug design and development.

  This group developed research on the conformations landscape of selective m-opioid agonists in gas phase and in aqueous solution (the fentanyl series). Here, the conformational characteristics responsible for high affinity -opioid binding of a series of fentanyl analogs were investigated using a combination of molecular mechanics and molecular dynamics techniques. In general, the fentanyl analogs favor a conformation that is quite different in gas phase, and in the presence of explicit solvent or lattice packing forces. The most active analogs were shown to possess an extended conformation, while fentanyl derivatives displayed reduced binding affinities are predicted to favor compact arrangements. A superposition of the proposed "bioactive conformations" across this ligand series identified the orientation of the N-phenethyl and the N-phenyl group to be a contributing factor responsible for the differential bind of the ohmefentanyl enantiomers, and other structural analogs. The 3-point pharmacophore model for the fentanyls also provided insights into the structure-activity relationship and served as a template for further QSAR and docking studies.