Abstract
The G-quadruplex DNA structures are mainly present at the terminal portion of telomeres and can be stabilized by ligands able to recognize them in a specific manner. The recognition process is usually related to the inhibition of the enzyme telomerase indirectly involved and over-expressed in a high percentage of human tumors. There are several ligands, characterized by different chemical structures, already reported in the literature for their ability to bind and stabilize the G-quadruplex structures. Using the structural and biological information available on these structures; we performed a high throughput in silico screening of commercially natural compounds databases by means of a structure-based approach followed by docking experiments against the human telomeric sequence d[AG3(T2AG3)3]. We identified 12 best hits characterized by different chemical scaffolds and conformational and physicochemical properties. All of them were associated to an improved theoretical binding affinity with respect to that of known selective G-binders. Among these hits there is a chalcone derivative; structurally very similar to the polyphenol butein; known to remarkably inhibit the telomerase activity.
Highlights
Telomeres are specialized DNA sequences that cap the ends of linear chromosomes and consist, in human and vertebrate, of highly conserved tandem repeats of the hexanucleotide d(TTAGGG)n [1,2,3,4].The guanines are over-represented in telomeres, and in promoter regions of genes, especially proto-oncogenes, such as c-myc, c-kit, bcl-2, VEGF, H-ras and N-ras, as well as in other human genes [5,6]
[61] PDB structure, where an intramolecular human telomeric DNA G-quadruplex in parallel conformation is in complex with two tetra-substituted naphthalene diimides (NDI), the first pharmacophore model generated automatically by LigandScout was characterized by nine features
The binding pocket characteristics and the protein-ligand interactions were identified with automatically-generated Maestro [98] 2D ligand interaction diagrams. These 2D representations of the binding pocket use distinctive colors and shapes to convey binding pocket shape, electrostatics and protein-ligand interactions. In this manuscript we developed some pharmacophore models starting from three experimental
Summary
Telomeres are specialized DNA sequences that cap the ends of linear chromosomes and consist, in human and vertebrate, of highly conserved tandem repeats of the hexanucleotide d(TTAGGG)n [1,2,3,4]. The most polymorphic G-quadruplexes are the unimolecular ones They are formed from the folding of a single guanine rich DNA or RNA sequence into a four-stranded quadruple helix structure with three connecting loops, that can adopt multiple topologies. In a recent publication we identified a new promising scaffold for G-quadruplex characterized by a psoralen moiety performing a high throughput in silico screening of commercially available molecules databases by merging ligand- and structure-based approaches by means of docking experiments [56] In this manuscript the available structural and biological information on G-quadruplex structures allowed us to perform a high throughput in silico screening of commercially natural compounds databases by means only of a structure-based approach followed by docking experiments against the human telomeric sequence d[AG3(T2AG3)3]. Twelve best candidates, associated to an improved theoretical binding affinity with respect to that of known selective G-binders, were identified and their biophysical and biological assays are in progress
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