Relative stability of G-quadruplex structures: Interactions between the human Bcl2 promoter region and derivatives of carbazole and diphenylamine.
The bcl2 promoter region forms a G-quadruplex structure, which is a crucial target for anticancer drug development. In this study, we provide theoretical predictions of the stability of different G-quadruplex folds of the 23-mer bcl2 promoter region and G-quadruplex ligand. We take into account the whole G-quadruplex structure, including bound-cations and solvent effects, in order to compute the ligand binding free energy using molecular dynamics simulation. Two series of the carbazole and diphenylamine derivatives are used to screen for the most potent drug in terms of stabilization. The energy analysis identifies the predominant energy components affecting the stability of the various different G-quadruplex folds. The energy associated with the stability of the G-quadruplex-K(+) structures obtained displays good correlation with experimental Tm measurements. We found that loop orientation has an intrinsic influence on G-quadruplex stability and that the basket structure is the most stable. Furthermore, parallel loops are the most effective drug binding site. Our studies also demonstrate that rigidity and planarity are the key structural elements of a drug that stabilizes the G-quadruplex structure. BMVC-4 is the most potential G-quadruplex ligand. This approach demonstrates significant promise and should benefit drug design.
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, 112, Taiwan; Institute of Biomedical informatics, National Yang-Ming University, Taipei, 112, Taiwan.
Sheh-Yi
SY
Sheu
Chao-Hsien
CH
Huang
Jia-Kai
JK
Zhou
Dah-Yen
DY
Yang
D001483:Base Sequence; D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism*; D004159:Diphenylamine / Q000737:chemistry / Q000378:metabolism*; D054856:G-Quadruplexes; D006801:Humans; D007477:Ions; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015335:Molecular Probes / Q000737:chemistry; D008969:Molecular Sequence Data; D009994:Osmolar Concentration; D011188:Potassium / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D055550:Protein Stability / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D055672:Static Electricity; D013816:Thermodynamics
D002227:Carbazoles; D007477:Ions; D008024:Ligands; D015335:Molecular Probes; D019253:Proto-Oncogene Proteins c-bcl-2; C041514:carbazole; D004159:Diphenylamine; D011188:Potassium
G-quadruplex; bcl2 promoter region; binding affinity; drug design; molecular dynamics