A1 Refereed original research article in a scientific journal

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



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.

Publisher: AMER CHEMICAL SOC

Publication year: 2023

Journal: Journal of Medicinal Chemistry

Journal name in source: JOURNAL OF MEDICINAL CHEMISTRY

Journal acronym: J MED CHEM

Volume: 66

Issue: 14

First page : 9784

Last page: 9796

Number of pages: 13

ISSN: 0022-2623

eISSN: 1520-4804

DOI: https://doi.org/10.1021/acs.jmedchem.3c00590

Web address : https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.3c00590

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/180392842


Abstract
Heteroaromatic stacking interactions are important indrug binding,supramolecular chemistry, and materials science, making protein-ligandmodel systems of these interactions of considerable interest. Herewe studied 30 congeneric ligands that each present a distinct heteroarenefor stacking between tyrosine residues at the dimer interface of procaspase-6.Complex X-ray crystal structures of 10 analogs showed that stackinggeometries were well conserved, while high-accuracy computations showedthat heteroarene stacking energy was well correlated with predictedoverall ligand binding energies. Empirically determined K (D) values in this system thus provide a useful measureof heteroarene stacking with tyrosine. Stacking energies are discussedin the context of torsional strain, the number and positioning ofheteroatoms, tautomeric state, and coaxial orientation of heteroarenein the stack. Overall, this study provides an extensive data set ofempirical and high-level computed binding energies in a versatilenew protein-ligand system amenable to studies of other intermolecularinteractions.

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Last updated on 2024-26-11 at 11:28