New insights into the structures of ligand-quadruplex complexes from molecular dynamics simulations.
G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences, and they are attractive anticancer drug targets. Understanding the three-dimensional interactions between a G-quadruplex and its ligand in solution is the key to discovering a drug lead. Hence, from crystallographic or NMR structures, molecular dynamics studies have been performed on six ligand-quadruplex complexes. BRACO-19, BSU6039, daunomycin, RHPS4, MMQ1, and TMPyP4 are the six ligands that bind to the G-quadruplex structures in the studies. Based on molecular dynamics simulations and a series of computational analyses, the results suggest that ions move away from the external G-quartet to let the ligand bind to the quadruplex in aqueous solution. The ligand binding can increase the stability of the Hoogseen hydrogen bonds within the G-quartet. However, the G-quartet binding site can only fit one ligand molecule. The ligand can form hydrogen bonds at the loop or flank of the quadruplex. However, not all the interactions will stabilize the ligand-quadruplex complex in aqueous solution. These findings can assist in the design of selective and potent G-quadruplex ligands.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Jin-Qiang
JQ
Hou
Shuo-Bin
SB
Chen
Jia-Heng
JH
Tan
Tian-Miao
TM
Ou
Hai-Bin
HB
Luo
Ding
D
Li
Jun
J
Xu
Lian-Quan
LQ
Gu
Zhi-Shu
ZS
Huang
D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D016615:Telomere / Q000737:chemistry / Q000235:genetics
D008024:Ligands; D004247:DNA