However, despite the high number of known ligands, none showed efficacy in cancer patients. Recent progress of targeted gquadruplexpreferred ligands. The in silico docking procedure can greatly reduce screening costs. In silico screening of quadruplexbinding ligands sciencedirect. Highlights we describe an in silico molecular docking method to identify g quadruplex binding ligands. Jan 30, 2020 some of the known efficient g quadruplex binding ligands namely tmpyp4, braco19, pds, etc. A database for gquadruplex structure forming nucleic. Dna damage and genome instability by gquadruplex ligands are. Therefore, this fret g quadruplex assay is a simple and effective approach to identify quadruplex binding ligands, and, as such, it promises to provide a solid foundation for the. Dna damage and genome instability by gquadruplex ligands. Identification of new natural dna gquadruplex binders. Structurebased approaches targeting oncogene promoter g. We have investigated the interplay of g4s with r loops, another noncanonical dna structure, and the.
Look for a run of 3 or more g followed by 1 to 7 of any other base, this all thing repeated 3 or more times and end with 3 or more g i have written a simple program to match regular expressions in a fasta file, its here fastaregexfinder. As a member of the wwpdb, the rcsb pdb curates and annotates pdb data according to agreed upon standards. Dna damage and genome instability by gquadruplex ligands are mediated by. A comprehensive and wellorganized database of gquadruplex ligands. For compatibility issues, visit test environmenttest. Variations in redundancy management schemes were examined analytically, and considerable simulator testing was performed for the baseline system at the. There is currently significant interest in the development of g.
Gquadruplex detection software tools rna structure data. G4ldb currently contains 800 gquadruplex ligands with 4000 activity records. In 4, 5 there is a detailed description of the gquadruplex structure. The gquadruplex 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. An online server for prediction and bioinformatics of unimolecular quadruplex forming nucleotide sequences. Nucleic acid g quadruplex structure g4 interacting proteins database g4ipdb is an important database that contains detailed information about proteins interacting with nucleic acids that forms. For license concerning java, marvin, jmol, and autodock, visit this page.
This article belongs to the special issue gquadruplex ligands and cancer. Approximately 1,000 various g quadruplex ligands exist in which they are able to interact via their aromatic rings. The gquadruplex ligands database g4ldb, provides a unique collection of reported gquadruplex ligands to streamline liganddrug discovery targeting gquadruplexes. Gquadruplexes are guaninerich nucleic acid sequences in human telomeres and gene promoter regions. A new method for the study of gquadruplex ligands deming kong, jing wu, yonge ma, and hanxi shen 1. Although the mb is a wellknown dna intercalator and has been previously reported to bind the gquadruplex, its application as a cmyc oncogenic promoter gquadruplex stabilizer was first discovered by our group. Gquadruplex dna and ligand interaction in living cells.
The type of arrangement found here is also likely to have relevance to ligand binding to loops in nontelomeric quadruplexes. A database for gquadruplex structure forming nucleic acid. These gquadruplex structures and their ligand complexes have been. The ligand database currently contains 800 reported gquadruplex ligands that are associated with 4000 related activity study records. Browse gquadruplex ligands gquadruplex ligands database.
Structural regulation by a gquadruplex ligand increases binding abilities of gquadruplexforming aptamers. In this study, we analyzed the presence and locations of gquadruplex. Mar 15, 2012 structural basis for telomeric g quadruplex targeting by naphthalene diimide ligands gavin w. We explored the cellular localization of phendc3, one of the most powerful g4 ligands, by synthesizing two clickable azide and alkyne derivs. The ligand database currently contains 800 reported g quadruplex ligands that are associated with 4000 related activity study records. Amongst local nonb dna structures, the significance of gquadruplexes was demonstrated in the last decade, and their presence and functional relevance has been demonstrated in many genomes, including humans. The role of local dna structures in the regulation of basic cellular processes is an emerging field of research. Guaninerich repetitive dna sequences are of particular importance at the ends of chromosomes, where they.
Palindrome analyzer tool for analyses of inverted repeats in dna sequences p53 binding predictor tool for searching and ranking p53 target sequence. Jan 15, 2019 in the past decades, several compounds have been developed specifically targeting g quadruplexes g4s, as these noncanonical dna structures are considered promising targets of effective anticancer drugs. Frontiers common gquadruplex binding agents found to. Jul 21, 2018 interactions of cationic tetraoylporphyrin derivatives with antiparallel gquadruplex pdb id 143d were studied by amd using dock6.
The tmpyp4 5,10,15,20tetrakis1methyl4pyridyl21h, 23hporphyrin is one ligand shown to be capable of binding to the g4structures. The recognition process is usually related to the inhibition of the enzyme telomerase indirectly involved and overexpressed in a high percentage of human tumors. Like its first version, grsdb, it contains information on composition and distribution of putative quadruplexforming grich sequences qgrs mapped in the. A database for discovering and studying gquadruplex. G4ipdb is the first database that provides comprehensive information. This is exemplified by the guaninerich sequence upstream from the promoter of the cmyc oncogene, 35 which is stabilised as an intrastrand foldback quadruplex by ligands such as the perylenediimide ligand piper. We compare the diversity of dna gquadruplex aptamers selected against multiple ligand targets, and consider structure with a particular focus on dissecting the thrombin binding aptamer thrombin interaction. Molecular docking based screening of triterpenoids as. 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. A number of smallmolecule ligands are described that stabilise quadruplex formation, and which result in telomerase inhibition. Molecular modeling and simulation of gquadruplexes and. The 3terminal region of the grich strand of human telomeres is singlestranded and may adopt a gquadruplex conformation. This facilitates cheminformatic studies and systemic analysis of gquadruplex ligands, and the search for novel binders. The presence and localization of gquadruplex forming.
Many of the reported g quadruplex ligands evaluated in biological essays have shown in vitro activities, including telomerase inhibition. The interaction between tmpyp4 and g4 has been extensively studied since it can inhibit the activity of telomerase upon binding to. Structural basis for telomeric gquadruplex targeting by naphthalene diimide ligands gavin w. Normalized cd spectra of gquadruplexforming sequences. The formation of a quadruplex structure at the 3 end of telomeric dna effectively hinders telomerase from adding further repeats. Using sofasthmqc type spectra, we probed a tetramolecular g quadruplex model made of dtg 4 t 4 inside living xenopus laevis oocytes. First, the overexpression of oncogenes like cmyc, ckit, and kras might be inhibited by promoter deactivation section 3. Evaluation of the selectivity of gquadruplex ligands in living cells.
A database for discovering and studying gquadruplex ligands. Cytotoxicity chemistrya european journal, 1430, 94319441 cytotoxicity chemistrya european journal, 1430, 94319441 activity cytotoxicity. Thereby, seven further novel g quadruplex ligands could be identified. Naphthalene diimide ligand bound to telomeric dna gquadruplex. A chemical structure left and schematic illustration right of a gtetrad, composed of four guanines linked together through hoogsteen hbonds red dashed lines. Quadruplex digital flight control system assessment. Cationic porphyrins bind guanine quadruplexes, but the effects of ligand binding on the structure of guanine quadruplexes with more than four contiguous guanine quartets remains to be fully elucidated.
Look for a run of 3 or more g followed by 1 to 7 of any other base, this all thing repeated 3 or more times and end with 3 or more g. Search and analyze transcribed regions of genes for putative qgrs quadruplex forming grich sequences near rna. Gquadruplexes, alternative dna secondary structures present in telomeres, emerge as promising targets for the treatment of cancer, because they prevent telomere elongation and accordingly cell proliferation. An effective system for assessing the targeting of gquadruplex ligands in. Click the analyze button after entering a valid nucleotide sequence for qgrs mapper to search for qgrs subsequences. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function.
G4im grinder fast, robust and highly adaptable algorithm. Ligands playing musical chairs with gquadruplex dna. Methods for the molecular modeling and simulation of gquadruplex structures and their drugligand complexes are discussed, and a range of protocols is presented for undertaking a variety of tasks including modelbuilding, ligand docking, dynamics simulation, continuum solvent modeling, energetic calculations, principal component analysis, and quantum chemical computations. Only a chemical database and a molecular docking algorithm are needed. Gquadruplex ligands mediate downregulation of dux4. We suggest that the present complex is thermodynamically favoured for crystal packing reasons. Our observations lead us to conclude that the quadruplex structure is formed within the cell and that the intracellular environment preferentially selects a conformation that most resembles the one found in.
Distance measurements between paramagnetic ligands bound. Representative examples of gquadruplex ligands identified by in silico screening. In this study, 208 glts were screened for ligands with high binding affinity and selectively to stabilize the pg4dna by using the docking tool autodock4. A disadvantage of using smallmolecule ligands as a therapeutic technique is that specificity is difficult to manage. Hi the gquadruplex sequence as defined in quadparser is effectively a regular expression, namely this one gg3,\w1,73,gg3, which means. G4 ligand from the mcule chemical database, by using simple docking programs. You are at the portal of the gquadruplex ligands database g4ldb. Users have the ability to search for standard proteinligand interactions, e. The server is designed to be userfriendly and needs minimal intervention by the user, while providing flexibility of defining the variants of the motif. This facilitates cheminformatic studies and systemic analysis of g quadruplex ligands, and the search for novel binders. Choose a target model gquadruplex ligands database. The original protocol was tested using various quadruplexand duplexdna targets, and with a wide panel of gquadruplex ligands belonging to different families i. Grsdb2 is a second generation database of gquadruplexes.
Gquadruplexes g4 are noncanonical nucleicacid structures found in guaninerich sequences. They are helical in shape and contain guanine tetrads that can form from one, two or four strands. Mentions figure 1 shows cd spectra of oligomers, the sequences of which are summarized in table 1. Identification and characterization of two conserved g. Abstract aside from a double helix, dna folds into noncanonical structures, one of which is the guanine quadruplex. Distance measurements between paramagnetic ligands bound to. Gquadruplex dna and ligand interaction in living cells using.
Two smallmolecule ligands, carboxy pyridostatin and rgb1, have been recently developed to specifically target rna gqs 78, 79. Normalized cd spectra of gquadruplexforming sequences openi. Being able to design software tools able in identifying such features may give the ability to predict the structure of a gquadruplex conformation. Quinazoline ligands induce cancer cell death through. This assay is based on the loss of fluorescence upon displacement of thiazole orange from quadruplex and duplexdna matrices. The gquadruplex ligands database g4ldb, provides a unique collection of reported gquadruplex ligands to streamline ligand drug discovery targeting gquadruplexes. G4 hunter web a new server with optimized g4hunter algorithm. The major findings are i protruding nucleotides destabilize the gquadruplex structure, and ii overhanging sequences influence the folding of the quadruplex. In this study, we analyzed the presence and locations of g quadruplex. Since the dux4 rna gqs are demonstrated to be a likely target of berberine that leads to its mrna downregulation, it would be interesting to evaluate these rna gq specificligands and their ability to suppress expression of the toxic transcription factor. An online server for prediction and bioinformatics of unimolecular quadruplexforming nucleotide sequences.
These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists. Hi the g quadruplex sequence as defined in quadparser is effectively a regular expression, namely this one gg3,\w1,73,gg3, which means. Some of the known efficient gquadruplex binding ligands namely tmpyp4, braco19, pds, etc. The gquadruplex resource site serves as a portal to our suite of software programs and databases for analysis of gquadruplexes. G quadruplex es g4 are noncanonical nucleicacid structures found in guaninerich sequences. Within this study, theoretically validated pharmacophore and shapebased models as well as a theoretically validated docking protocol were generated and applied in parallel for virtual. Therefore, this fret gquadruplex assay is a simple and effective approach to identify quadruplexbinding ligands, and, as such, it promises to provide a solid foundation for the.
G4s can play a regulatory role in basic nuclear functions such as replication and. Tmpyp4 k d 50 nm and pds k d 70 nm bound more tightly to the quadruplex form than 4 bound to the hairpin k d 260 nm tables 2 and s1. Interactions of cationic tetraoylporphyrin derivatives with antiparallel gquadruplex pdb id 143d were studied by amd using dock6. The design of gquadruplex ligands as telomerase inhibitors. Structural studies of naphthalene diimide ligands with. The 3terminal region of the grich strand of human telomeres is singlestranded and may adopt a g quadruplex conformation.
Representative examples of g quadruplex ligands identified by in silico screening. G4ipdb also provides an efficient webbased gquadruplex predictor. These molecules do not only represent novel scaffolds, but some of them are in addition even more potent g quadruplex stabilizers than the established reference compound berberine. It offers a user friendly interface that can meet a variety of data inquiries from researchers. Conducted as the basic task under nas2i1853, the effort focused on critical pitchaxis functions for a relaxed static stability transport. Li q1, xiang jf, yang qf, sun hx, guan aj, tang yl. Combined data from fluorescence measurements and cd spectroscopy indicated that ligands selected by this fret method could induce gdna to form a gquadruplex. In molecular biology, gquadruplex secondary structures g4 are formed in nucleic acids by sequences that are rich in guanine. Cationic porphyrins bind guanine quadruplexes, but the effects of ligand binding on the structure of guanine quadruplexes with more than four contiguous guanine quartets remains to. We describe an in silico molecular docking method to identify gquadruplex binding ligands. Trap chemistrya european journal, 1430, 94319441 trap chemistrya european journal, 1430, 94319441 in cellulo properties. This method can rapidly identify potential gquadruplex binding ligands. Kaori tsukakoshi, yuri ikuta, koichi abe, wataru yoshida, keisuke iida, yue ma, kazuo nagasawa, koji sode and kazunori ikebukuro materials and.
The evidence of cooperative binding of a ligand to g4 dna. In this study, a set of biophysical assays was applied to evaluate the binding of six drug. The rcsb pdb also provides a variety of tools and resources. Normalized cd spectra of g quadruplex forming sequences in brittonrobinson buffer containing 50 mm kcl, ph 7. G4 ligands acting as reporters, for tracking both in vitro and in cells. Nucleic acid gquadruplex structure g4 interacting proteins database g4ipdb is an important database that contains detailed information about. Quadfinder enables users to discover g quadruplex motifs in any sequence of interest. G4ldb currently contains 800 g quadruplex ligands with 4000 activity records. Targeting human telomeric gquadruplex dna could be one of the mechanisms by which these glts exert anticancer activity. Optimized virtual screening workflow for the identification. Highlights we describe an in silico molecular docking method to identify gquadruplex binding ligands. Methods for the molecular modeling and simulation of g quadruplex structures and their drugligand complexes are discussed, and a range of protocols is presented for undertaking a variety of tasks. Hampel, marialuisa micco, stephen neidle, and gary n.
Powerful geometric search criteria can be used to mine public and proprietary data for measurements, e. Methods for the molecular modeling and simulation of gquadruplex structures and their drugligand complexes are discussed, and a range of protocols is presented for undertaking a variety of tasks. Combined data from fluorescence measurements and cd spectroscopy indicated that ligands selected by this fret method could induce gdna to form a g quadruplex. This method can rapidly identify potential g quadruplex binding ligands. A comprehensive and wellorganized database of g quadruplex ligands. Structure of a gquadruplexligand complex sciencedirect. The unimolecular forms often occur naturally near the ends of the chromosomes, better known as the telomeric regions, and in transcriptional regulatory regions of. The structure has a single drug molecule bound per quadruplex, i. The original protocol was tested using various quadruplex and duplexdna targets, and with a wide panel of g quadruplex ligands belonging to different families i. A database for discovering and studying gquadruplex ligands article pdf available in nucleic acids research 41database issue november 2012 with 301 reads how we measure reads. However, these databases focus on the motifs and sequences of gquadruplexes rather than on gquadruplex ligands. Using sofasthmqc type spectra, we probed a tetramolecular gquadruplex model made of dtg 4 t 4 inside living xenopus laevis oocytes. Methods for the molecular modeling and simulation of g quadruplex structures and their drugligand complexes are discussed, and a range of protocols is presented for undertaking a variety of tasks including modelbuilding, ligand docking, dynamics simulation, continuum solvent modeling, energetic calculations, principal component analysis, and quantum chemical computations.
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