5 research outputs found
Mapping Functional Group Free Energy Patterns at Protein Occluded Sites: Nuclear Receptors and G‑Protein Coupled Receptors
Occluded ligand-binding pockets (LBP)
such as those found in nuclear
receptors (NR) and G-protein coupled receptors (GPCR) represent a
significant opportunity and challenge for computer-aided drug design.
To determine free energies maps of functional groups of these LBPs,
a Grand-Canonical Monte Carlo/Molecular Dynamics (GCMC/MD) strategy
is combined with the Site Identification by Ligand Competitive Saturation
(SILCS) methodology. SILCS-GCMC/MD is shown to map functional group
affinity patterns that recapitulate locations of functional groups
across diverse classes of ligands in the LBPs of the androgen (AR)
and peroxisome proliferator-activated-γ (PPARγ) NRs and
the metabotropic glutamate (mGluR) and β<sub>2</sub>-adreneric
(β<sub>2</sub>AR) GPCRs. Inclusion of protein flexibility identifies
regions of the binding pockets not accessible in crystal conformations
and allows for better quantitative estimates of relative ligand binding
affinities in all the proteins tested. Differences in functional group
requirements of the active and inactive states of the β<sub>2</sub>AR LBP were used in virtual screening to identify high efficacy
agonists targeting β<sub>2</sub>AR in Airway Smooth Muscle (ASM)
cells. Seven of the 15 selected ligands were found to effect ASM relaxation
representing a 46% hit rate. Hence, the method will be of use for
the rational design of ligands in the context of chemical biology
and the development of therapeutic agents