We report here crystal structures of a g quadruplex selective ligand complexed with two human telomeric dna quadruplexes. Author links open overlay panel stephen neidle gary n. We are the providers of genome analysis software, protein structure prediction tool, insillico drug design software, drug discovery, bioinformatics, bioinformatics, algorithms for genome analysis, active site directed drug design, gene to drug, bioinformatics and computational biology facility, super computer access, research and development in bioinformatics, computational pathways for life. Gquadruplexes are dna secondary structures formed by guaninerich sequences, for example, within gene promoters where they may contribute to transcriptional activity. To assess the effects of a threenucleotide ttt linker, the crystal structure of the dna sequence dg4t3g4 has been determined at 1. Structure of the first parallel dna quadruplexdrug complex. The present study reports the enhancement of the pharmacological properties of earlier nd compounds using structure based design. Fm represents a useful tool in drug discovery, especially when obtaining an. To screen and design ligands of unsolved g quadruplex structures, homology modelling methods may also be applied to extend the target g quadruplex structure and, therefore, provide more screening models. Topology variation and loop structural homology in crystal.
The in silico methods for drug discovery are becoming increasingly. Guaninerich dna sequences can fold into fourstranded, noncanonical secondary structures called gquadruplexes g4s. However, most recent results from the encode project indicate that only 3% of human genome is expressed in protein and that rna and dna may form noncanonical secondary structures that are functionally important. Deviating from watsoncrick hydrogen bonding found in bform duplex. Sequence, stability, structure of gquadruplexes and their. The structure of the bsu6039quadruplex dna complex was solved by molecular replacement by means of the program epmr.
As drug design targets, the topology and structural characteristics of quadruplexes, their possible biological roles, and the modes and sites of smallligand binding to these structures should be understood clearly. Design and applications of noncanonical dna base pairs. Computational approaches to predict the noncanonical dnas. Implications for drug design are discussed, in the context of the druggability of both telomeric and nontelomeric quadruplex. The first crystal structure of a drug daunomycin bound to a parallelstranded intermolecular telomeric g4 quadruplex dtggggt4 has been determined to high resolution. G quadruplex ligand research is an emerging field in the discovery of novel drugs. Quadruplex dna has been proposed to be important in telomere structure and function, in the regulation of gene expression and in some triplet repeat diseases. However, in the crystal structure, ligands at the 5. Crystal structures of three complexes with human telomeric intramolecular quadruplexes demonstrate that two of the four strongly basic nmethylpiperazine groups can be replaced by less basic morpholine groups with. One such example is the fourstranded g quadruplex dna. Crystallographic studies of g quadruplex nucleic acids have resulted in a small group of structures to date.
Quadruplex dnas have been implicated in a number of biological processes. The proximal promoter of vegfr2 contains a g quadruplex, which has been suggested to interact with small molecules that inhibit vegfr2 expression and thereby tumor angiogenesis. The crystal structure of the second zdna binding domain of human dai zbp1 in complex with zdna reveals an unusual binding mode to zdna. Although dna is most widely known to store and pass along genetic information, the discovery of g quadruplex structures has illuminated a new role of dna in biology yang and okamoto 2010.
We provide a variety of data inquiry methods for you to efficiently retrieve, analyze, and design g quadruplex ligands. Structural basis of dna quadruplex recognition by an. The first crystal structure of a drug daunomycin bound to a parallelstranded intermolecular. A very high density of gquadruplexes at telomeres along with their large exposed.
A putative gquadruplex structure in the proximal promoter. The energy function and its parameterization with an overview of the program. Recently, structurebased drug design using the crystal structure of the. Highlights we survey the recent literature on molecular modeling of drugdna interactions. The crystal structure of the parallel stranded propellertype quadruplex formed from the human telomeric sequence dag 3 t 2 ag 3 3 pdb id. They are helical structures containing guanine tetrads that can form from one, two or four strands. Guanine quadruplex an overview sciencedirect topics. Gquadruplexes are noncannonical fourstranded dna or rna structures. The unimolecular forms often occur naturally near the ends of the chromosomes. Crystal structure of the major quadruplex formed in the.
It is a common feature of most native quadruplex crystal structures that when packed into the crystal lattice the 5. Knowledge of the biologically relevant topology is critical for the design of drugs targeting quadruplex nucleic acids. Request pdf quadruplex dna crystal structures and drug design crystallographic studies of g quadruplex nucleic acids have resulted in a small group of structures to date. The discovery of the bdna structure in 1953 1 provided an explanation of basic. Improvements to the apbs biomolecular solvation software suite. Highly specific and tightbinding nucleic acid aptamers have been selected against a variety of molecular targets for over 20 years. Although many of these structures were determined, the chairtype g quadruplex structure remains elusive. Quadruplex dna crystal structures and drug design core. The g4ldb, with systematically collected information of reported g quadruplex ligands, provides a useful resource for the study of g quadruplex ligands. The crystal structure of one complex revealed a square planar geometry of the nickel ion. We aim at spearheading your drug ligand discovery efforts for g quadruplex. More carefully designed controls will be needed to assess whether a. Crystal structure of parallel quadruplexes from human.
The nuclease hypersensitivity element iii 1 nhe iii 1 of the cmyc promoter can form transcriptionally active and silenced forms, and the formation of dna g quadruplex structures has been shown to be critical for cmyc transcriptional silencing. Considerable circumstantial evidence suggests that these structures can exist in vivo in specific regions of the genome including the telomeric ends of chromosomes and oncogene regulatory regions. Three more drug complex crystal structures with human telomeric quadruplexes have very recently been solved pdb ids 3cdm, 3cco, 3ce5 in this laboratory parkinson et al. Evidence of kinetically controlled ligand binding and bindingmode assisted quadruplex structure alteration. Gquadruplex dna as a target for drug design request pdf. Tanner department of biochemistry, university of hong kong, pokfulam, hong kong, china abstract. Unimolecular parallelstranded g quadruplex structures are found to be prevalent in gene promoters. Methods for the molecular modeling and simulation of g quadruplex structures and their drug ligand 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. Selective recognition and stabilization of new ligands.
In molecular biology, gquadruplex secondary structures g4 are formed in nucleic acids by sequences that are rich in guanine. In this study, the ability of two anthraquinone telomerase inhibitors nsc749235 and nsc764638 to target telomeric gquadruplex dna was probed. Pymol is an invaluable opensource software tool for making structurebased hypotheses. Structure of a gquadruplexligand complex sciencedirect. However, certain dna sequences that are purine rich and contain runs of guanines g can form fourstranded structures that are called gquadruplexes. The crystal structure is in general agreement with the solution nmr structure. Demonstration that drugtargeted downregulation of myc in.
The sole published crystal structure, of the tmpyp412mer complex, is in the same parallel arrangement as found in the native structure. A planar assemblage of three daunomycin molecules stacks onto the 5 end of the g4 column, with the daunosamine substituents occupying three of the four quadruplex grooves. Parkinson gn 2008 quadruplex dna crystal structures and drug design. Computational methods to study gquadruplexligand complexes. Gtetrad surfaces tend to be stacked against each other. Ligand binding to telomeric gquadruplex dna investigated by. Molecules free fulltext the amino acid composition of. The xray crystal structure of the g4 ligand mm41 bound to a human. G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology.
Analysis of the genome of the social amoeba dictyostelium discoideum indicates a low number of sequences with g4forming potential 2491055. Crystal structure of the major quadruplex formed in the promoter. In silico methods applied to triplex, g quadruplex and minor groove binders. Biqun zou, hong liang, synthesis, crystal structure and biological evaluation of a new dasatinib copperii complex as. Virtual screening and structure based design for the identification of novel scaffolds. However, there are no highresolution complex structures reported for g quadruplex ligands except for a docked bsu6037. Implications for drug design are discussed, in the context of the druggability of both telomeric and. Structural basis of dna quadruplex recognition by an acridine drug article in journal of the american chemical society 21. Loop flexibility in human telomeric quadruplex small. Consequently, it was also observed in the crystal structure of parallel. Methods for the molecular modeling and simulation of g quadruplex structures and their drug ligand complexes are discussed, and a range of protocols is presented for undertaking a variety of tasks.
Chemical and structural studies provide a mechanistic. Finding and characterizing the complexes of drug like. Regulation of catalytic activity and processivity of human telomerase. It is a unique, comprehensive and wellorganized database of g quadruplex ligands. Gquadruplexes are fourstranded globular nucleic acid secondary structures, formed by one or more dna molecules figure 1. Computer aided drug design is a helpful tool in novel drug discovery and has been used. When selecting a quadruplex target, the question becomes. Binding of telomestatin, tmpyp4, bsu6037, and braco19 to. Dna is widely recognized as a doublehelical structure with a crucial role in genetic information storage. Understanding ligand interaction with different structures of g quadruplex dna.
We felt that targeting this protrusion would allow the docking program. Modeling and design of peptidomimetics to modulate proteinprotein interactions. The g quadruplex dna structures were stabilized in. The crystal structure provides an alternative model that, along with comparisons to other reported quadruplex crystal structures, will be important to the rational design of selective compounds. Structure of the first parallel dna quadruplexdrug. Gquadruplexes g4s are noncanonical dna structures that frequently occur in the promoter regions of oncogenes, such as myc, and regulate gene. Quadruplexes are fourstranded dna or rna structures formed from tandem. Molecular modeling and simulation of gquadruplexes and.
You are at the portal of the g quadruplex ligands database g4ldb. The development of a ligand that is capable of distinguishing among the wide variety of gquadruplex structures and targeting telomeres to treat cancer is particularly challenging. The crystal structure of the second z dna binding domain of human dai zbp1 in complex with z dna reveals an unusual binding mode to z dna. Dna is most often regarded as a duplex molecule in which the two selfcomplementary strands are held together by watsoncrick base pairs. Quadruplex nucleic acids as targets for anticancer.
Currently, there are over 200 crystal and nmrderived structures of. The implications for rational drug design of quadruplexbinding ligands are clear. Quadruplex dna structures were first observed more than 50 years ago, but have only relatively recently attracted interest for their role in the development of. Quadruplexes can be formed from one, two or four separate strands of dna or rna and can display a wide variety of topologies, which are in part a consequence of various possible combinations of strand direction, as well as variations in loop size and sequence. Telomeric dna sequences can form fourstranded quadruplex structures 2,3,4, which may be involved in the structure of telomere ends 5. Structure based design of selective and potent g quadruplex mediated telomerase inhibitors martin read, r. Computer aided drug design is a helpful tool in novel drug discovery and has been used to screen and design g quadruplex ligands 19,33,34. Guaninerich dna has the potential to fold into noncanonical g quadruplex g4 structures. Dna gquadruplex and its potential as anticancer drug target.
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