IntroductionThis article discusses the process of defining competencies and development
of a best practices training course for investigators and clinical research
coordinators who conduct social and behavioral research.MethodsThe first project phase established recommendations for training in Good
Clinical Practice (GCP) and was done in conjunction with representatives
from 62 Clinical and Translational Science Award (CTSA) hubs. Diversity in
behavioral clinical trials and differences in regulation of behavioral
trials compared with clinical trials involving drugs, devices, or biologics
necessitated a separate Social and Behavioral Work Group. This group worked
with CTSA representatives to tailor competencies and fundamental GCP
principles into best practices for social and behavioral research.ResultsAlthough concepts underlying GCP were deemed similar across all clinical
trials, not all areas were equally applicable and the ways in which GCP
would be enacted differ for behavioral trials. It was determined that
suitable training in best practices for social and behavioral research was
lacking.DiscussionBased on the training need, an e-learning course for best practices is
available to all CTSA sites. Each institution is able to track outcomes for
its employees to help achieve standardized competency-based best practices
for social and behavioral investigators and staff.
Heteroaromatic stacking interactions are important in
drug binding,
supramolecular chemistry, and materials science, making protein–ligand
model systems of these interactions of considerable interest. Here
we studied 30 congeneric ligands that each present a distinct heteroarene
for stacking between tyrosine residues at the dimer interface of procaspase-6.
Complex X-ray crystal structures of 10 analogs showed that stacking
geometries were well conserved, while high-accuracy computations showed
that heteroarene stacking energy was well correlated with predicted
overall ligand binding energies. Empirically determined K
D values in this system thus provide a useful measure
of heteroarene stacking with tyrosine. Stacking energies are discussed
in the context of torsional strain, the number and positioning of
heteroatoms, tautomeric state, and coaxial orientation of heteroarene
in the stack. Overall, this study provides an extensive data set of
empirical and high-level computed binding energies in a versatile
new protein–ligand system amenable to studies of other intermolecular
interactions.
Heteroaromatic stacking interactions help stabilize protein tertiary structure and are important in drug binding, supramolecu-lar chemistry, and materials science. Although diverse computational and experimental approaches have been utilized to study these interactions, a broadly useful protein–ligand model system has yet to emerge, despite laudable efforts by Diederich and co-workers in this vein. Here we studied thirty synthetic ligands that present diverse heteroarene probes for stacking between symmetry-related tyrosine residues at the dimer interface of procaspase-6. We demonstrate crystallograph-ically that stacking geometries are highly conserved across the ligand test set and show with high-accuracy computations that differences in ligand binding free energies are primarily attributable to the relative strength of the stacking interactions. The empirical results are discussed in light of recent computational studies of these interactions, including the effects of torsional strain, heteroarene tautomeric state, and co-axial orientation of stacking groups. Overall, this study provides an extensive dataset of empirical and high-level computed binding energies in a versatile new protein–ligand system highly amenable to studies of other intermolecular interactions.
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