Molecular Simulation Study On The Mechanism Of Organic Ligand Targeting DNA G-Quadruplex

Human DNA G-quadruplexes have been an attractive drug target for cancer therapeutic intervention. Especially the G-quadruplex groove has been paid growing attention to because of its selectivity. With the development of computer, molecular docking and molecular dynamics simulation have been applied in the study of the interaction mechanism between drug ligand and macromolecular and drug design. In this work, the mechanism of drug ligand targeting the groove of DNA G-quadruplex and the selectivity of 4-benzylpiperidine antagonists for hCCR3 were studied.1. In this work, molecular dynamics (MD) simulations of different sequences of G-quadruplexes ([d(TGGGGT)]4 and [d(GGGGGG)]4) complex with distamycin A (Dist-A) dimmers were performed. The characteristics of drug binding in G-quadruplex groove was investigated. The simulations revealed that in the [d(TGGGGT)]4 groove, Dist-A located in the floor of the groove and the N3 atom of guanine base in the 3'-end of the groove can form stable hydrogen bond with the formyl amino terminus of Dist-A. While in the groove of [d(GGGGGG)]4, Dist-A dimmer located in the 5'-end of the groove, and the formyl amino terminus of L2 is repulsed by the guanine base in the middle of the groove and forms hydrogen bond (L2NH1-4/A_G3:O2P) with the phosphate backbone of the opposite strand A. The MD results indicates that it is more favorable for the binding of Dist-A in the end of groove. The density functional theory (DFT) method at the B3LYP/6-31G (d, p) level was utilized to estimate electronic properties of guanine bases of three successive G-tetrads. It is suggested that N3 atoms of guanine bases in the middle G-tetrad layers have less negative charge than that in the terminal ones, which would have disadvantageous effect for the binding of the formyl amino terminus of Dist-A in the middle groove of G-quadruplex. This study proposes the factors affecting the binding of drugs in the G-quadruplex groove, and is of significance for drug design based on the structure of G-quadruplex groove.2. The binding mechanism of Dist-A and Dist-A derivative B in human telomeric DNA antiparallel G-quadruplex were studied by molecular docking and molecular dynamics (MD) simulation. MD simulation indicated that Dist-A canπ-stacking interact with the end of the quartet, while Dist-A derivative B interact with antiparallel G-quadruplex in L shape (stacking on the end of the quartet and binding in the groove). The analysis of the widths of different complexes showed that in the complexes of ligands binding in wide and meddle grooves, the interactions of ligands and the backbones of loops change the widths of the grooves, while in the complexes of ligands binding in narrow groove, the width of groove were changed by the interaction between ligand and groove. MM_PBSA calculation indicated that Dist-A derivative B can stabilize the antiparallel G-quadruplex more than Dist-A. The entropy is more favorable for groove binding.3. The mechanisms of Steroid FG interaction with mixed hybrid-type DNA G-quadruplex and B-DNA were studied using molecular docking and molecular dynamics (MD) simulation. The selectivity of Steroid FG for hybrid-type DNA G-quadruplex and B-DNA was discussed. The results showed that in the hybrid-type DNA G-quadruplex, Steroid FG bound in the region between groove and flank loop with the mode of the two methyls on the fused ring facing to the quartet, while in the B-DNA, Steroid FG bound in the TA minor groove with the flank of the fused ring for the floor of groove. MM_PBSA calculation indicated that the complex of Steroid FG and G-quadruplex had lower binding free energy and more favorable binding entropy. This work may provide useful principles for drug designing based on G-quadruplex groove.4. The "antagonist-bound" three-dimensional models of the hCCR3 and hCCRl receptors were constructed by homology modeling, using the X-ray structure of bovine rhodopsin as the template, and refined with MM/MD methods. We also carried out an automated docking of several 1,4-disubstituted piperidine antagonists into the hCCR3 and hCCRl model. The binding hypothesis and the reliability of the hCCR3 model were confirmed by the reasonable correlation between the estimated binding free energy and the experimental -1gIC50 values (R2=0.94). The docking results reveal that the face-to-face Vander Waals interaction between piperidine ring and Tyr255 plays an important role on the selectivity of 4-phenzylpiperidine antagonists to hCCR3. Simultaneously, the more hydrophobic of the EL2 in hCCR3 is favorable for the selectivity of 4-phenzylpiperidine antagonists. This work would be beneficial for the rational design of hCCR3 receptor antagonist.