Systematic Study of Heteroarene Stacking Using a Congeneric Set of Molecular Glues for Procaspase‑6

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...

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Published inJournal of medicinal chemistry Vol. 66; no. 14; pp. 9784 - 9796
Main Authors Togo, Takaya, Tram, Linh, Denton, Laura G., ElHilali-Pollard, Xochina, Gu, Jun, Jiang, Jinglei, Liu, Chenglei, Zhao, Yan, Zhao, Yanlong, Zheng, Yinzhe, Zheng, Yunping, Yang, Jingjing, Fan, Panpan, Arkin, Michelle R., Härmä, Harri, Sun, Deqian, Canan, Stacie S., Wheeler, Steven E., Renslo, Adam R.
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 27.07.2023
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Ligands
Models, Molecular
Pharmacology & Pharmacy
Proteins - metabolism
Science & Technology
Tyrosine
BENZENE
HETEROCYCLES
RECOGNITION
ACTIVE-SITE
QRET
AROMATIC RINGS
PI-PI INTERACTIONS
ATOM
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Summary: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.
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c00590