8AAD

Two carbons pendant pyridine derivative of the natural alkaloid Berberine as Human Telomeric G-quadruplex Binder

Summary for 8AAD

• Entry DOI: 10.2210/pdb8aad/pdb
• Related: 6S15 7ZUR
• Descriptor: DNA TAGGGTTAGGGT, POTASSIUM ION, 16,17-dimethoxy-21-(2-pyridin-4-ylethyl)-5,7-dioxa-13$l^{4}-azapentacyclo[11.8.0.0^{2,10}.0^{4,8}.0^{15,20}]henicosa-1(13),2,4(8),9,14,16,18,20-octaene, ... (4 entities in total)
• Functional Keywords: drug-dna complex, telomeric g-quadruplex, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 4293.16

Authors

Ferraroni, M.,Bazzicalupi, C.,Gratteri, P.,Papi, F. (deposition date: 2022-07-01, release date: 2022-12-07, Last modification date: 2024-01-31)

Primary citation

Bazzicalupi, C.,Bonardi, A.,Biver, T.,Ferraroni, M.,Papi, F.,Savastano, M.,Lombardi, P.,Gratteri, P.
Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: The interaction between the series of berberine derivatives - (NAX071, NAX120, NAX075, NAX077 and NAX079) and human telomeric G-quadruplexes (G4), which are able to inhibit the Telomerase enzyme's activity in malignant cells, was investigated. The derivatives bear a pyridine moiety connected by a hydrocarbon linker of varying length ( = 1-5, with number of aliphatic carbon atoms) to the C13 position of the parent berberine. As for the G4s, both bimolecular 5'-TAGGGTTAGGGT-3' (Tel12) and monomolecular 5'-TAGGGTTAGGGTTAGGGTTAGGG-3' (Tel23) DNA oligonucleotides were considered. Spectrophotometric titrations, melting tests, X-ray diffraction solid state analysis and in silico molecular dynamics (MD) simulations were used to describe the different systems. The results were compared in search of structure-activity relationships. The analysis pointed out the formation of 1:1 complexes between Tel12 and all ligands, whereas both 1:1 and 2:1 ligand/G4 stoichiometries were found for the adduct formed by NAX071 ( = 1). Tel12, with tetrads free from the hindrance by the loop, showed a higher affinity. The details of the different binding geometries were discussed, highlighting the importance of H-bonds given by the berberine benzodioxole group and a correlation between the strength of binding and the hydrocarbon linker length. Theoretical (MD) and experimental (X-ray) structural studies evidence the possibility for the berberine core to interact with one or both G4 strands, depending on the constraints given by the linker length, thus affecting the G4 stabilization effect.

PubMed: 36430540
DOI: 10.3390/ijms232214061

Experimental method

X-RAY DIFFRACTION (2.04 Å)