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Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis.

ABSTRACT: Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function-2 through the residues Phe737 and Gln738. Without ligand or with agonist binding, H12 swings from inward to outward to visit different folding positions. However, the binding of RU486 or AZD9567 perturbs the structural state, and the passive antagonist state appears more stable. Structure-based virtual screening and in vitro bioassays are used to discover novel GR ligands that bias the conformation equilibria toward the passive antagonist state. HP-19 exhibits the best anti-inflammatory activity (IC₅₀ = 0.041 ± 0.011 µm) in nuclear factor-kappa B signaling pathway, which is comparable to that of DEX. HP-19 also does not induce adverse effect-related transactivation functions of GR. The novel ligands discovered here may serve as promising starting points for the development of GR modulators.

SUBMITTER: Hu X

PROVIDER: S-EPMC8787434 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Among the polycyclic aromatic hydrocarbon class of chemical carcinogens, dibenzo[a,l]pyrene (DB[a,l]P) is the most potent tumorigen that has been identified to date. Structurally, it is bulky with six aromatic rings, and it contains the nonplanar fjord-region. The conformational properties of DB[a,l]P-derived DNA adducts responsible for its extraordinary carcinogenicity are hence of great interest. We have carried out molecular modeling and MD simulations for the 14R (+)- and 14S (-)-trans-anti-DB[a,l]P-N?-dA adducts derived from the reactions of the DB[a,l]P diol epoxides with adenine in double-stranded DNA. The structures are based on the classically intercalated NMR solution structures of the analogous fjord-region benzo[c]phenanthrene-derived-N?-dA adducts. One objective was to gain insight on the impact of the more bulky DB[a,l]P ring system on the structural characteristics of the intercalative adduct conformations. A further objective was to elucidate the effect of the flexible twist associated with the sterically hindered aromatic ring in the fjord-region on the intercalated conformations, for comparison with the intercalated but planar bay-region benzo[a]pyrene-derived-N?-dA adducts. For the DB[a,l]P-N?-dA adducts, our results show that the 14R (+)-adduct is more favorably intercalated on the 5'-side of the modified adenine than the stereoisomeric 14S (-)-adduct, intercalated on its 3'-side. The 14R (+)-adduct manifests better van der Waals stacking interactions with flanking base pairs, less perturbed Watson-Crick hydrogen bonding, less local groove enlargement, less unwinding, and a lower solvent exposure than the 14S (-)-adduct. These structural findings are consistent with observed thermodynamic melting data, UV absorption properties, and fluorescence quenching studies. By contrast, the NMR solution structures for the analogous but less bulky B[c]Ph-derived adducts reveal no such stereoisomeric effect, while the planar bay-region benzo[a]pyrene-derived-N?-dA adducts do. Differences in nucleotide excision repair susceptibilities of the fjord and bay region adducts stem from distinctions in their intercalative conformations, produced by the intrinsic topological variations in their polycyclic aromatic ring systems.

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Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis.

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