title: Structural and energetic insights into sequence-specific interaction in DNA-drug recognition: development of affinity predictor and analysis of binding selectivity.
abstract: Although the molecular mechanism and thermodynamic profile of a wide variety of chemical agents have been examined intensively in the past decades in terms of specific recognition of their protein receptors, to date the physicochemical nature of DNA-drug recognition and association still remains largely unexplored. The present study focused on understanding the structural basis, energetic landscape, and biological implications underlying the binding of small-molecule ligands to their cognate or non-cognate DNA receptors. First, a new method to capture the structural features of DNA-drug complex architecture was proposed and then used to correlate the extracted features with binding affinity of the complexes. By employing this method, a statistical regression-based predictor was developed to quantitatively evaluate the interaction potency of drug compounds with DNA in a fast and reliable manner. Subsequently, we use the predictor to examine the binding behavior of a number of structure-available, affinity-known DNA-drug complexes as well as a large pool of randomly generated DNA decoys in complex with the same drugs. It was found that (1) as compared with protein-DNA recognition, small-molecule agents have relatively low specificity in selecting their cognate DNA targets from the background of numerous random decoys; (2) the abundance of A-T base pairs in the DNA core motif exhibits a significant positive correlation with the affinity of drug ligand binding to the DNA receptor; and (3) high affinity seems not to be closely related to high selectivity for a DNA-targeting drug, although high-affinity drug entities have a greater possibility of being ranked computationally as top binders. We hope that this work will provide a preliminary insight into the molecular origin of sequence-specific interactions in DNA-drug recognition.
authors.affiliation: School of Chemical and Biological Engineering, Changsha University of Science and Technology, Changsha 410004, China.
authors.forename: Jingheng
authors.initials: J
authors.lastname: Ning
authors.forename: Weiwei
authors.initials: W
authors.lastname: Chen
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Li
authors.forename: Zaixi
authors.initials: Z
authors.lastname: Peng
authors.forename: Jianhui
authors.initials: J
authors.lastname: Wang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ni
mesh_terms: D020029:Base Pairing; D001550:Benzamidines / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009429:Netropsin / Q000737:chemistry*; D009690:Nucleic Acid Conformation; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
chemical_list: D001550:Benzamidines; D008024:Ligands; D009429:Netropsin; C033286:furamidine; D004247:DNA; C005555:propamidine