Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 55, Issue 3, Pages 700-708Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ci500729k
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Funding
- NIH [GM051501, CA107331, HL104119, AG041265]
- Maryland Industrial Partnerships Award 5212
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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-gamma (PPAR?) NRs and the metabotropic glutamate (mGluR) and beta(2)-adreneric (beta(2)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 beta(2)AR LBP were used in virtual screening to identify high efficacy agonists targeting beta(2)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.
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