Halogen Bonding in Nucleic Acid Complexes

Journal of Medicinal Chemistry, Год журнала: 2017, Номер 60(21), С. 8681 - 8690

Опубликована: Июнь 12, 2017

Halogen bonding (X-bonding) has attracted notable attention among noncovalent interactions. This highly directional attraction between a halogen atom and an electron donor been exploited in knowledge-based drug design. A great deal of information gathered about X-bonds protein–ligand complexes, as opposed to nucleic acid complexes. Here we provide thorough analysis complexes containing either halogenated building blocks or ligands. We analyzed close contacts halogens electron-rich moieties. The phosphate backbone oxygen is clearly the most common acceptor. identified 21 within known structures vast majority formed by nucleobases, such bromouridine, feature excellent geometries. Noncovalent ligands have found form only interactions with suboptimal interaction Hence, first X-bonded binder remains be discovered.

Язык: Английский

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Energy landscapes of homopolymeric RNAs revealed by deep unsupervised learning

Biophysical Journal, Год журнала: 2024, Номер 123(9), С. 1152 - 1163

Опубликована: Апрель 3, 2024

Язык: Английский

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Specific Interaction between a Fluoroquinolone Derivative, KG022, and RNAs with a Single Bulge

Biochemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Small compounds targeting RNAs are recognized as a promising modality in drug discovery. We have found that fluoroquinolone derivative, KG022, binds to with single-bulged residues. It has been demonstrated by 1H NMR KG022 bulged G or C and GC AU base pair at the 3′ adjacent In present study, effects of pairs 5′ residues on interaction were analyzed mainly NMR. was prefers UA CG residues, indicating stable complex is formed stacking among ring purine bases sides. addition, this confirmed analysis 19F-NMR spectra. Analysis temperature dependences spectra revealed forms more having position than those pairs. This work presented useful information for development small molecules higher affinity target RNAs.

Язык: Английский

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Advanced strategies for screening and identifying RNA-targeted small molecules: Bridging therapeutic potential and innovation

Results in Chemistry, Год журнала: 2025, Номер unknown, С. 102305 - 102305

Опубликована: Апрель 1, 2025

Язык: Английский

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Novel Inhibitors of SARS-CoV-2 RNA Identified through Virtual Screening

Journal of Chemical Information and Modeling, Год журнала: 2024, Номер 64(15), С. 6190 - 6196

Опубликована: Июль 22, 2024

We currently lack antivirals for most human viruses. In a quest new molecules, focusing on viral RNA, instead of proteins, can represent promising strategy. this study, inhibitors were identified starting from published crystal structure the tertiary SARS-CoV-2 RNA involved in -1 programmed ribosomal frameshift. The pseudoknot was refined, and virtual screening performed using repository binders to nucleic acid library, taking into consideration flexibility. Hit compounds validated against wild-type virus with dual-luciferase assay measuring frameshift efficiency. Several active molecules identified. Our study reveals but also highlights feasibility targeting screening, strategy that could be broadly applied drug development.

Язык: Английский

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Decoding the genome of SARS-CoV-2: a pathway to drug development through translation inhibition

RNA Biology, Год журнала: 2024, Номер 21(1), С. 1 - 18

Опубликована: Дек. 4, 2024

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the disease 2019 (COVID-19) pandemic and is continuously spreading globally. continuous emergence of new SARS-CoV-2 variants keeps posing threats, highlighting need for fast-acting, mutation-resistant broad-spectrum therapeutics. Protein translation vital replication, producing early non-structural proteins RNA replication transcription, late structural virion assembly. Targeted blocking viral protein thus a potential approach to developing effective anti-SARS-CoV-2 drugs. SARS-CoV-2, as an obligate parasite, utilizes host's machinery. Translation-blocking strategies that target mRNA, especially those its conserved elements are generally preferred. In this review, we discuss current understanding translation, important motifs structures involved in regulation. We also through degradation or element dysfunction.

Язык: Английский

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The Structure-to-Function Relationships of Gammaherpesvirus-Encoded Long Non-Coding RNAs and their Contributions to Viral Pathogenesis

Опубликована: Сен. 1, 2018

Advances in next-generation sequencing have facilitated the discovery of a multitude long non-coding RNAs (lncRNAs) with pleiotropic functions cellular processes, disease and viral pathogenesis. It came as no surprise when viruses were also revealed to transcribe their own lncRNAs. Among them, gammaherpesviruses, one three subfamilies Herpesviridae, code largest number. These structurally functionally intricate (nc) transcripts modulate gene expression maintain latency or prompt lytic reactivation. The lncRNAs allow virus escape cytosolic surveillance, sequester re-localize essential factors cell cycle proliferation. Some act “messenger molecules”, transferring information about infection neighboring cells. This broad range lncRNA is achieved through structure-mediated interactions effector molecules host origin, including other RNAs, proteins DNAs. In this review, we discuss examples gammaherpesvirus-encoded lncRNAs, emphasize unique structural attributes, link them life cycle, pathogenesis progression. We will address potential novel targets for drug propose future directions explore structure function relationship.

Язык: Английский

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Mapping energy landscapes of homopolymeric RNAs via simulated tempering and deep unsupervised learning

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 10, 2023

ABSTRACT Conformational dynamics plays crucial roles in RNA functions about sensing and responding to environmental signals. The liquid-liquid phase separation of RNAs the formation stress granules partly relies on RNA’s conformational plasticity its ability engage multivalent interactions. Recent experiments with homopolymeric low-complexity have revealed significant differences separations due base chemistry units. We hypothesize that phase-transition can be traced back single chains. In present contribution, we utilize atomistic simulations numerous unsupervised learning map temperature dependence free energy landscapes for These reveal a variety metastable excited states influenced by nature chemistry. shed light distinct contributions polyphosphate backbone versus shaping ensembles different RNAs. demonstrate experimentally observed temperature-driven shifts state populations align experimental diagrams work establishes microscopic framework reason base-specific propensity separation. believe our will valuable designing novel sensors biological synthetic applications.

Язык: Английский

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Tying the knot: Unraveling the intricacies of the coronavirus frameshift pseudoknot

PLoS Computational Biology, Год журнала: 2024, Номер 20(5), С. e1011787 - e1011787

Опубликована: Май 7, 2024

Understanding and targeting functional RNA structures towards treatment of coronavirus infection can help us to prepare for novel variants SARS-CoV-2 (the virus causing COVID-19), any other coronaviruses that could emerge via human-to-human transmission or potential zoonotic (inter-species) events. Leveraging the fact all use a mechanism known as −1 programmed ribosomal frameshifting (−1 PRF) replicate, we apply algorithms predict most energetically favourable secondary (each nucleotide involved in at one pairing) may be regulating PRF event coronaviruses, especially SARS-CoV-2. We compute previously unknown stable structure predictions frameshift site hierarchical folding, biologically motivated framework where initial non-crossing folds first, followed by subsequent, possibly crossing (pseudoknotted), structures. Using mutual information from 181 sequences, conjunction with algorithm KnotAli, different coronaviruses. then utilize Shapify obtain guided sequence-specific genome-wide experimental data. build on our previous investigation singular 68 nt element sequence, using 132 extended sequences including covariation information. Previous investigations have not applied folding length sequences. By doing so, simulate effects ribosome interaction site, providing insight biological function. contribute in-depth discussion contextualize dual-graph motifs SARS-CoV-2, highlighting energetic stability identified 3_8 motif alongside dominant 3_3 3_6 (native-type) combination thermodynamic methods sequence covariation, suggest function attenuator hairpin pseudoknotted base pairing. While certain is consistent, pairs form which indicate conformational switching between two

Язык: Английский

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Perspectives on Applications of 19F-NMR in Fragment-Based Drug Discovery

Molecules, Год журнала: 2024, Номер 29(23), С. 5748 - 5748

Опубликована: Дек. 5, 2024

Fragment-based drug discovery is a powerful approach in discovery, applicable to wide range of targets. This method enables the potent compounds that can modulate target functions, starting from fragment bind weakly While biochemical, biophysical, and cell-based assays are commonly used identify fragments,

Язык: Английский

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