Triplex Selective 2-(2-Naphthyl)quinoline Compounds:  Origins of Affinity and New Design Principles

Chaires, Jonathan B.; Ren, Jinsong; Henary, Maged; Zegrocka, Oliwia; Bishop, G. Reid; Strękowski, Lucjan

doi:10.1021/ja034181r

Cited by 60 publications

(65 citation statements)

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“…An alternative strategy uses ligands which bind selectively to triplex (not duplex) DNA and which therefore perturb the equilibrium in the direction of triplex formation. Several such ligands have been described (reviewed in [14]) including 3-methoxy-7H-8-methyl-11[(3¢-amino)propylamino]-benzo [e]pyrido [4,3-b]indole 2 (BePI) and its derivatives [15][16][17][18], coralyne [19][20][21], naphthylquinoline derivatives [22][23][24][25][26] and bis-substituted amidoanthraquinones [27,28]. Although most studies with these compounds have examined their interaction with parallel triplets, they also stabilize the antiparallel motif [24,25,29].…”

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confidence: 99%

DNA sequence specificity of triplex‐binding ligands

Keppler

James

Neidle

et al. 2003

European Journal of Biochemistry

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We have examined the ability of naphthylquinoline, a 2,7-disubstituted anthraquinone and BePI, a benzo[e]pyridoindole derivative, to stabilize parallel DNA triplexes of different base composition. 1Fluorescence melting studies, with both inter-and intramolecular triplexes, show that all three ligands stabilize triplexes that contain blocks of TAT triplets. Naphthylquinoline has no effect on triplexes formed with third strands composed of (TC) n or (CCT) n , but stabilizes triplexes that contain (TTC) n . In contrast, BePI slightly destabilizes the triplexes that are formed at (TC) n (CCT) n and (TTC) n . 2,7-Anthraquinone stabilizes (TC) n (CCT) n and (TTC) n , although it has the greatest effect on the latter. DNase I footprinting studies confirm that triplexes formed with (CCT) n are stabilized by the 2,7-disubstituted amidoanthraquinone but not by naphthylquinoline. Both ligands stabilize the triplex formed with (CCTT) n and neither affects the complex with (CT) n . We suggest that BePI and naphthylquinoline can only bind between adjacent TAT triplets, while the anthraquinone has a broader sequence of selectivity. These differences may be attributed to the presence (naphthylquinoline and BePI) or absence (anthraquinone) of a positive charge on the aromatic portion of the ligand, which prevents intercalation adjacent to C + GC triplets. The most stable structures are formed when the stacked rings (bases or ligand) alternate between charged and uncharged species. Triplexes containing alternating C + GC and TAT triplets are not stabilized by ligands as they would interrupt the alternating pattern of charged and uncharged residues.Keywords: anthraquinone; molecular beacon; naphthylquinoline; triple helix; triplex-binding ligand.The formation of intermolecular DNA triple helices offers a means for designing agents which can bind to specific DNA sequences [1][2][3][4][5][6]. In this approach, a third strand oligonucleotide binds in the major groove of duplex DNA, forming specific hydrogen bond contacts with substituents on the purines of the duplex base pairs. In these structures the third strand can run either parallel or antiparallel to the duplex purine strand. Parallel triplexes, which have been most widely studied, consist of TAT and C + GC triplets, while the antiparallel motif contains GGC and AAT or TAT triplets. Although triplex-forming oligonucleotides bind to their duplex targets with considerable sequence selectivity, their binding may not be strong. Several strategies have therefore been used to improve their affinity, including the use of base and backbone analogues [7][8][9][10], and tethering DNA binding agents such as acridine [11,12] or psoralen [13] to the end of the oligonucleotide. An alternative strategy uses ligands which bind selectively to triplex (not duplex) DNA and which therefore perturb the equilibrium in the direction of triplex formation. Several such ligands have been described (reviewed in [14]) including 3-methoxy-7H-8-methyl-11 [(3¢-amino) [27,28]. Although most studies with the...

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confidence: 99%

DNA sequence specificity of triplex‐binding ligands

Keppler

James

Neidle

et al. 2003

European Journal of Biochemistry

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“…Institute of Organic Chemistry, Moscow, Russia). As positive controls, the known triplex selective ligands MHQ-15 and OZ-85H were synthesized as previously described [44].…”

Section: Virtualmentioning

confidence: 99%

“…Either of these approaches could be used to control gene expression. These capabilities make these small molecules potentially clinically relevant performed an extensive study that characterized the selectivity and affinity of 14 napthylquinoline derivatives [44]. The ligand MHQ-12 emerged from that study as the compound with the highest affinity and greatest selectivity for the poly(dA)-[poly(dT)h triplex.…”

Section: Introductionmentioning

confidence: 99%

“…The quantitative metric that is used for evaluating Surflex-Sim results is the Surflex-Sim score, which embodies an all atom comparison and alignment of the test ligand with the control ligand. The top ranked Surflex-Sim results were used for structure-based docking studies to dock the ligand to the intercalation site and the three grooves (major-major, major-minor and minor) of the triplex structure using the docking program Surflex-Dock [44]. Surflex-Dock performs docking of test ligands to a "protomol" or idealized representation of the binding site on the nucleic acid target.…”

Section: Introductionmentioning

confidence: 99%

“…In this chapter, both ligand and structure based virtual screening techniques are combined as well as utilizing the established in silica selectivity metrics to discover new triplex nucleic acid binding small molecules. Chaires et al have previously identified a set of napthylquinoline ligands that were demonstrated by competition dialysis to be highly selective triplex poly(dA)-[poly(dT)h intercalators [44]. One of these napthlyquinolines in particular, MHQ-12, was used as the parental ligand in a similarity search against millions of in silica compounds.…”

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Determination of in silico rules for predicting small molecule binding behavior to nucleic acids in vitro.

Holt¹

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The vast knowledge of nucleic acids is evolving and it is now known that DNA can adopt highly complex, heterogeneous structures. Among the most intriguing are the G-quadruplex structures, which are thought to playa pivotal role in cancer pathogenesis.Efforts to find new small molecules for these and other physiologically relevant nucleic acid structures have generally been limited to isolation from natural sources or rationale synthesis of promising lead compounds.However, with the rapid growth in computational power that is increasingly becoming available, virtual screening and computational approaches are quickly becoming a reality in academia and industry as an efficient and economical way to discover new lead compounds. These computational efforts have historically almost entirely focused on proteins as targets and have neglected DNA. We present research here showing that not only can software be utilized for targeting DNA, but that selectivity metrics can be developed to predict the binding mechanism of a small molecule to a DNA target. The software Surflex and Autodock were chosen for evaluation and were demonstrated to be able to accurately reproduce the known crystal structures of several small molecules that bind by the most common nucleic acid interacting mechanisms of groove binding and intercalation. These software IV were further used to rationalize known affinity and selectivity data of a 67 compound library of compounds for a library of nucleic acid structures including duplex, triplex and quadruplexes. Based upon the known binding behavior of these compounds, in silica metrics were developed to classify compounds as either groove binders or intercalators.These rules were subsequently used to identify new triplex and quadruplex binding small molecules by structure and ligand-based virtual screening approaches using a virtual library consisting of millions of commercially available small molecules. The binding behavior of the newly discovered triplex and quadruplex binding compounds was empirically validated using a number of spectroscopic, fluorescent and thermodynamic equilibrium techniques. In total, this research predicted the binding behavior of these test compounds in silica and subsequently validated these findings in vitro. This research presents a novel approach to discover lead compounds that target multiple nucleic acid morphologies.

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DNA‐Conjugated Organic Chromophores inDNAStacking Interactions

Filichev

Pedersen

2008

Wiley Encyclopedia of Chemical Biology

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Since the discovery of the intercalation of acridine derivatives into DNA (1961), chemists have synthesized many intercalators tethered to DNA. Advances in the chemical synthesis of modified nucleosides along with progress in oligonucleotide synthesis have made it possible to introduce organic chromophores in any desired position of the sequence. As an outcome of such fascinating research, we gained a deeper knowledge and understanding of nucleic acid structures, which is pivotal for future progress within nucleic acid technology and for development of novel approaches in drug design. The current review presents those efforts in the design of intercalators/organic chromophores as oligonucleotide conjugates that form a foundation for the generation of novel nucleic acid architectures.

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Triplex Selective 2-(2-Naphthyl)quinoline Compounds: Origins of Affinity and New Design Principles

Cited by 60 publications

References 56 publications

DNA sequence specificity of triplex‐binding ligands

DNA sequence specificity of triplex‐binding ligands

Determination of in silico rules for predicting small molecule binding behavior to nucleic acids in vitro.

DNA‐Conjugated Organic Chromophores inDNAStacking Interactions

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