This facilitates cheminformatic studies and systemic analysis of g quadruplex ligands, and the search for novel binders. The unimolecular forms often occur naturally near the ends of the chromosomes. A focused library of analogs of a leadlike g quadruplex g4 targeting compound 4, sharing a furobenzoxazine naphthoquinone core and differing for the pendant groups on the natom of the. Hi the g quadruplex sequence as defined in quadparser is effectively a regular expression, namely this one gg3,\w1,73,gg3, which means. Nov 21, 2016 g quadruplexes are increasingly recognized as regulatory elements in human, animal, bacterial and plant genomes. Only a chemical database and a molecular docking algorithm are needed. May 01, 2012 highlights we describe an in silico molecular docking method to identify g quadruplex binding ligands.
Piper is able to promote the formation of dimeric g quadruplex structures at low drugoligomer ratios, while at higher ratios it promotes exclusively the formation of tetrameric g quadruplex structures. Combined data from fluorescence measurements and cd spectroscopy indicated that ligands selected by this fret method could induce gdna to form a g quadruplex. The identification of these sequences as novel targets for the development of anticancer drugs has sparked great interest in the design of molecules that can interact with quadruplex dna. We provide a variety of data inquiry methods for you to efficiently retrieve, analyze, and design g quadruplex ligands.
A very high density of gquadruplexes at telomeres along with their large exposed planar. Each tetrad is composed of four g residues that are linked by the sugarphosphate backbone and connected through. G4 stabilization by smallmolecule compounds called g4 ligands often causes cytotoxicity. To this end, the development of new g4 ligands has attracted extensive research. Author summary gquadruplexes are nucleic acid noncanonical structures that have been implicated in the regulation of different biological processes of many organisms. Gquadruplexes are guaninerich nucleic acid sequences in human telomeres and gene promoter regions.
Targeting gquadruplex dna structures in the telomere and. Their presence has been demonstrated also in several viral pathogens, providing new insights into viruses biology and potentially serving as drug targets. Normalized cd spectra of g quadruplex forming sequences in brittonrobinson buffer containing 50 mm kcl, ph 7. You are at the portal of the g quadruplex ligands database g4ldb. Genomewide analysis of gquadruplexes in herpesvirus genomes. Qgrs mapper is a userfriendly application that provides many options for defining and studying g quadruplexes. A database for gquadruplex structure forming nucleic acid. A new method for the study of gquadruplex ligands deming kong, jing wu, yonge ma, and hanxi shen 1. Gquadruplex forming sequences in the genome of all known. G quadruplexes are guaninerich nucleic acid sequences in human telomeres and gene promoter regions. Gquadruplex g4 structures are fourstranded noncanonical dna structures enriched at telomeres and oncogenes promoters. In addition, the extent of binding of these ligands to various g4 dnas was determined, thus substantiating the biophysical results.
The gquadruplex resource site serves as a portal to our suite of software programs and databases for analysis of gquadruplexes. Some of the known efficient gquadruplex binding ligands namely tmpyp4, braco19, pds, etc. We provide a variety of data inquiry methods for you to efficiently retrieve, analyze, and design gquadruplex ligands. Gquadruplex ligands mediate downregulation of dux4. In silico screening of quadruplexbinding ligands, methods. Predicts quadruplex forming g rich sequences qgrs in nucleotide sequences. It is a unique, comprehensive and wellorganized database of gquadruplex ligands. Gquadruplex prediction bioinformatics tools rna structure. The ligand database currently contains 800 reported g quadruplex ligands that are associated with 4000 related activity study records. G quadruplexes are guaninerich nucleic acid sequences in human telomeres and gene.
The in silico docking procedure can greatly reduce screening costs. Improvements to the apbs biomolecular solvation software suite. They are helical structures containing guanine tetrads that can form from one, two or four strands. It is also designed to handle the analysis of mammalian premrna sequences, including that are alternatively processed alternatively spliced or alternatively polyadenylated. A database for discovering and studying gquadruplex. Jul 21, 2018 braco19 is a 3,6,9trisubstituted acridine derivative, designed by neidle et al. G quadruplexes g4s and r loops are noncanonical dna structures that. The targeting of four typical ligands to gquadruplexes in live cells was. A database for gquadruplex structure forming nucleic. G4ldb currently contains 800 g quadruplex ligands with 4000 activity records. All four dna strands are parallel, with the three linking trinucleotide loops positioned on the exterior of the quadruplex core, in a propellerlike arrangement. Targeting glioma stem cells in vivo by a gquadruplex. Although experimental validation is needed to confirm the actual. Diklung ma, victor puiyan ma, kaho leung, haijing zhong, hongzhang he, daniel shiuhin chan and chunghang leung january 24th 20.
This article belongs to the special issue gquadruplex ligands and cancer. It offers a user friendly interface that can meet a variety of data inquiries from researchers. G4ipdb also provides an efficient webbased gquadruplex predictor. We have investigated the interplay of g4s with r loops, another noncanonical dna structure, and the. Structural analysis and cellular visualization of app rna g. G quadruplex structures couple a common scaffold to varying loop motifs that act in target recognition. G4 hunter web a new server with optimized g4hunter algorithm. Browsing gquadruplex ligands and checking information for a specified ligand. You are at the portal of the gquadruplex ligands database g4ldb. 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. Ischapp is a gquadruplextriggered fluorogenic hybridization gtfh probe that is made up of two parts fig. The signal transducer and activator of transcription 3 stat3 protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to dna damage. Representative examples of g quadruplex ligands identified by in silico screening. Dec 17, 2014 since potential therapeutic significance had been discovered for quadruplex secondary structures of nucleic acids, many compounds stabilizing these targets were identified.
Recent progress of targeted gquadruplexpreferred ligands. One of the two ligands is markedly less mobile in the crystal complex and is more quadruplex stabilizing, forming multiple electrostatichydrogen bond contacts with quadruplex phosphate groups. 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. In the human genome, guaninerich sequences with the potential to form g quadruplexes exist in the telomere as well as in promoter regions of certain oncogenes. These gquadruplex structures and their ligand complexes have been. Identification and characterization of two conserved g. 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. The progress was due to understanding the structural features of g quadruplexes. The g quadruplex g4 structures of nucleic acids are considered to play an intrinsic role in gene expression. In silico screening of quadruplexbinding ligands request pdf. This method can rapidly identify potential g quadruplex binding ligands. Development of squaraine based gquadruplex ligands using.
Despite a recent explosion of interest in g quadruplex dna, most fundamental questions regarding the possible presence and function of these intriguing structures in vivo remain unanswered. A new method for the study of gquadruplex ligands deming kong,a, bjing wu, yonge mab and hanxi shen received 18th march 2008, accepted 15th april 2008 first published as an advance article on the web 24th april 2008 doi. G4ldb currently contains 800 gquadruplex ligands with 4000 activity records. Gquadruplex g4 is a higherorder nucleic acid structure that is formed by guaninerich sequences. More than 800 gquadruplex ligands are currently included in the g4ldb. Gquadruplex ligand cell cycleapoptosis modulators chemietek. P53 binding predictor tool for searching and ranking p53 target sequence. Nov 17, 2012 the g quadruplex ligands database g4ldb, provides a unique collection of reported g quadruplex ligands to streamline liganddrug discovery targeting g quadruplexes. The proximal promoter region of the human vascular endothelial growth factor gene has a gquadruplex structure that can be targeted by gquadruplexinteractive agents mol. Here we show that phendc3, a g quadruplex ligand structurally unrelated to heme, displaces quadruplex bound heme in vitro and alters transcription in cultured human cells, upregulating genes that support heme degradation and iron homeostasis, and most strikingly causing a 30fold induction of heme oxidase 1, the key enzyme in heme degradation. It performs analysis of the user provided genomic sequences, e. It is capable of locating, identifying, qualifying and quantifying dna and rna potential quadruplex structures, such as gquadruplex, imotifs and their higher. Structurebased approaches targeting oncogene promoter g. However, these databases focus on the motifs and sequences of gquadruplexes rather than on gquadruplex ligands.
Qgrs mapper is a software program that generates information on composition and distribution of putative quadruplex forming grich sequences qgrs in nucleotide sequences. In molecular biology, gquadruplex secondary structures g4 are formed in nucleic acids by sequences that are rich in guanine. Palindrome analyzer tool for analyses of inverted repeats in dna sequences. Pdf the gquadruplex ligands database g4ldb, provides a unique collection of reported gquadruplex ligands to. It is the first rationally designed telomerase inhibitor 30 that exhibited strong antitumor activity. Structurebased approaches targeting oncogene promoter g quadruplexes, oncogene and cancer from bench to clinic, yahwardiah siregar, intechopen, doi.
Grsdb2 is a second generation database of gquadruplexes. Quadruplex ligands selectively suppress the growth of tumor cells by indirectly attenuating telomerase activity or inhibiting oncogene. This work, presents the first evidence of extended g quadruplex sites in key regions of the hsv1 genome, indicates the possibility to block viral dna replication by g quadruplex ligand and therefore provides a proof of concept for the use of g quadruplex ligands as new antiherpetic therapeutic options. However, despite the high number of known ligands, none showed efficacy in cancer patients. Computational methods to study gquadruplexligand complexes. Normalized cd spectra of gquadruplexforming sequences openi.
Targeting g quadruplex dna with small molecules nathan w. We performed genomewide analysis of putative quadruplex sequences pqs. In cancer cells, stabilization of g4 dnas leads to replication stress. Putative dna gquadruplex formation within the promoters of. The gquadruplex ligands database g4ldb, provides a unique collection of reported gquadruplex ligands to streamline ligand drug discovery targeting gquadruplexes. Crystal structure of an intramolecular human telomeric dna gquadruplex 21mer bound by the naphthalene diimide compound mm41. A comprehensive and wellorganized database of g quadruplex ligands. An intriguing effect of g4 ligands is the induction of dna damage and. Stable and conserved gquadruplexes in the long terminal. Evaluation of the selectivity of gquadruplex ligands in living cells. Sequences in the hsp90 promoter form gquadruplex structures with selectivity for disubstituted phenyl bisoxazole derivatives. Interaction of metal complexes with gquadruplex dna. G4im grinder fast, robust and highly adaptable algorithm.
Sequences in the hsp90 promoter form gquadruplex structures. The presence and function of g quadruplexes are not well studied among herpesviruses. A comprehensive and wellorganized database of gquadruplex ligands. A database for discovering and studying gquadruplex ligands article pdf available in nucleic acids research 41database issue november 2012 with 287 reads how we measure reads. A focused library of analogs of a leadlike gquadruplex g4 targeting compound 4, sharing a furobenzoxazine naphthoquinone core and differing for the pendant groups on the natom of the. It is a unique, comprehensive and wellorganized database of g quadruplex ligands.
To investigate the most probable modes of binding of these ligands to various gquadruplex structures at the telomeric and oncogene promoter regions, we performed docking studies using the autodock 4. Dna damage and genome instability by gquadruplex ligands are. A significant proportion of these oligonucleotides display g quadruplex structures, particularly for dna aptamers, that enable molecular recognition of their ligands. Li q1, xiang jf, yang qf, sun hx, guan aj, tang yl. These results confirm the ability of the pqs in the upstream b regions of the var genes to fold in g quadruplexes, and show that g quadruplex ligands are likely to bind to these structures within the p. G4ipdb is the first database that provides comprehensive information. 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. Quinazoline ligands induce cancer cell death through. By single clicking the browse gquadruplex ligands button, users will find tables listing the gquadruplex ligands that compose the g4ldb figure 1e.
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