Structured Waters Mediate Small Molecule Binding to G-Quadruplex Nucleic Acids

Neidle, Stephen

doi:10.3390/ph15010007

Cited by 23 publications

(13 citation statements)

References 136 publications

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“…Both NDI complexes involve two individual G4 units stacking at the 5′ G-quartet interface in a process mediated by a coordinating potassium ion. In these structures, many of the NDI side-chains are placed within the G4s groove regions, interacting through different hydrogen bonds, water bridges, and electrostatic contacts with the negatively charged phosphate groups, as previously reported for other branched fused polycyclic aromatic ligands [ 185 ].…”

Section: G4-ligand Complexes and Intermolecular Interaction Modesmentioning

confidence: 81%

“…Additionally, the length and the nature of the bi and tri side chains terminal groups, many functionalized with tertiary amine moieties fully protonated at physiological pH, boost the affinity and the binding energetics to the DNA and RNA G4 grooves ( Figure 8 A). Interestingly, several different structures found at the RCSB databank [ 192 ], evidence that these cationic groups do not directly interact with the G4 phosphates, but instead with bridging water molecules found intercalating the pairs of bases in the flexible grooves, which were shown to play important roles in G4 ligand interactions [ 185 ].…”

Section: G4-ligand Complexes and Intermolecular Interaction Modesmentioning

confidence: 99%

“…In this regard, Neidle has recently pointed out that these studies consider only the isolated G4 structures, which does not reflect the cellular environment in which G4s are embedded with duplex DNA, folded mRNA, or chromatin contexts [ 184 ]. Moreover, special attention must be paid when choosing the G4 structure to be used in computer-assisted design of G4-interactive molecules since clusters of structured water molecules play essential roles in mediating the interaction between ligand side chains groups chromophore core and G-quadruplex [ 185 ].…”

Section: Introductionmentioning

confidence: 99%

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Major Achievements in the Design of Quadruplex-Interactive Small Molecules

et al. 2022

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Organic small molecules that can recognize and bind to G-quadruplex and i-motif nucleic acids have great potential as selective drugs or as tools in drug target discovery programs, or even in the development of nanodevices for medical diagnosis. Hundreds of quadruplex-interactive small molecules have been reported, and the challenges in their design vary with the intended application. Herein, we survey the major achievements on the therapeutic potential of such quadruplex ligands, their mode of binding, effects upon interaction with quadruplexes, and consider the opportunities and challenges for their exploitation in drug discovery.

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Section: G4-ligand Complexes and Intermolecular Interaction Modesmentioning

confidence: 81%

Section: G4-ligand Complexes and Intermolecular Interaction Modesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Major Achievements in the Design of Quadruplex-Interactive Small Molecules

et al. 2022

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“…In this arrangement, multiple bridging waters facilitate the polar secondary amine (at the 4-position of the quinazoline) and ethoxy group that are projecting away from the mostly non-polar cavity (Figs 4 and 5 , & S6 Fig ). Although it might seem counterintuitive that so much of the binding interaction is facilitated by water bridges, a recent assessment of high resolution DNA G4 crystal structure complexes showed that the 1 st and 2 nd shell waters play essential roles in stabilizing ligand-G4 interactions [ 86 ]. Thus, the structural insights gained from explicit solvent MD of ligand-G4 interactions and SiteMap [ 74 , 75 ] analyses are highly beneficial for future medicinal chemistry efforts.…”

Section: Discussionmentioning

confidence: 99%

Drug discovery of small molecules targeting the higher-order hTERT promoter G-quadruplex

et al. 2022

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DNA G-quadruplexes (G4s) are now widely accepted as viable targets in the pursuit of anticancer therapeutics. To date, few small molecules have been identified that exhibit selectivity for G4s over alternative forms of DNA, such as the ubiquitous duplex. We posit that the lack of current ligand specificity arises for multiple reasons: G4 atomic models are often small, monomeric, single quadruplex structures with few or no druggable pockets; targeting G-tetrad faces frequently results in the enrichment of extended electron-deficient polyaromatic end-pasting scaffolds; and virtual drug discovery efforts often under-sample chemical search space. We show that by addressing these issues we can enrich for non-standard molecular templates that exhibit high selectivity towards G4s over other forms of DNA. We performed an extensive virtual screen against the higher-order hTERT core promoter G4 that we have previously characterized, targeting 12 of its unique loop and groove pockets using libraries containing 40 million drug-like compounds for each screen. Using our drug discovery funnel approach, which utilizes high-throughput fluorescence thermal shift assay (FTSA) screens, microscale thermophoresis (MST), and orthogonal biophysical methods, we have identified multiple unique G4 binding scaffolds. We subsequently used two rounds of catalogue-based SAR to increase the affinity of a disubstituted 2-aminoethyl-quinazoline that stabilizes the higher-order hTERT G-quadruplex by binding across its G4 junctional sites. We show selectivity of its binding affinity towards hTERT is virtually unaffected in the presence of near-physiological levels of duplex DNA, and that this molecule downregulates hTERT transcription in breast cancer cells.

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“…An interdependence between the functions of biomolecules and their hydration waters is now well recognized (Chaplin, 2006;Raschke, 2006;Ball, 2008;Biedermannova ´& Schneider, 2016;Laage et al, 2017;Persson et al, 2018;Zsido ´& Hete ´nyi, 2021;Yamamoto et al, 2021). Water molecules are known to influence folding and recognition between biomolecules (Levy & Onuchic, 2006;Hummer, 2010), and they mediate DNApeptide recognition (Khesbak et al, 2011) and interactions between DNA and minor-groove binders (Nguyen et al, 2009;Wei et al, 2013;Neidle, 2021). Release of partially ordered water from the hydrated layer upon the binding of interacting partners is a source of entropic force (Leikin et al, 1993;Dunitz, 1994).…”

Section: Introductionmentioning

confidence: 99%

Knowledge-based prediction of DNA hydration using hydrated dinucleotides as building blocks

Biedermannová

Černý

Malý

et al. 2022

Acta Crystallogr D Struct Biol

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Water plays an important role in stabilizing the structure of DNA and mediating its interactions. Here, the hydration of DNA was analyzed in terms of dinucleotide fragments from an ensemble of 2727 nonredundant DNA chains containing 41 853 dinucleotides and 316 265 associated first-shell water molecules. The dinucleotides were classified into categories based on their 16 sequences and the previously determined structural classes known as nucleotide conformers (NtCs). The construction of hydrated dinucleotide building blocks allowed dinucleotide hydration to be calculated as the probability of water density distributions. Peaks in the water densities, known as hydration sites (HSs), uncovered the interplay between base and sugar-phosphate hydration in the context of sequence and structure. To demonstrate the predictive power of hydrated DNA building blocks, they were then used to predict hydration in an independent set of crystal and NMR structures. In ten tested crystal structures, the positions of predicted HSs and experimental waters were in good agreement (more than 40% were within 0.5 Å) and correctly reproduced the known features of DNA hydration, for example the `spine of hydration' in B-DNA. Therefore, it is proposed that hydrated building blocks can be used to predict DNA hydration in structures solved by NMR and cryo-EM, thus providing a guide to the interpretation of experimental data and computer models. The data for the hydrated building blocks and the predictions are available for browsing and visualization at the website https://watlas.datmos.org/watna/.

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Structured Waters Mediate Small Molecule Binding to G-Quadruplex Nucleic Acids

Cited by 23 publications

References 136 publications

Major Achievements in the Design of Quadruplex-Interactive Small Molecules

Major Achievements in the Design of Quadruplex-Interactive Small Molecules

Drug discovery of small molecules targeting the higher-order hTERT promoter G-quadruplex

Knowledge-based prediction of DNA hydration using hydrated dinucleotides as building blocks

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