Computer-aided design of RNA-targeted small molecules: A growing need in drug discovery

Manigrasso, Jacopo; Marcia, Marco; Vivo, Marco De

doi:10.1016/j.chempr.2021.05.021

Cited by 50 publications

(42 citation statements)

References 159 publications

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“…Systematic studies should now follow up to gain direct molecular insights into these transcripts. To facilitate these progresses, especially in the required highthroughput perspective, a game-changing role could be played by computational innovation, to analyze the diversity of lncRNAs at the genetic and structural, molecular level using machine-learning driven or artificial-intelligence driven algorithms [25,26]. Such studies would have the potential to foster personalized therapeutic approaches in a targeted, precision-medicine-based fashion.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…Recent medicinal chemistry and pharmacological research has progressed in the development and refinement of RNA-targeted small molecule libraries, identified compounds that specifically bind and regulate RNA, and successfully optimized some of these compounds for therapeutic use [25,26]. Although the primary RNA pharmacological targets remain ribozymes and riboswitches, the identification of structured lncRNAs, as reviewed above, opens the door for exploiting also this more newly discovered class of transcripts in the clinics, particularly in oncology.…”

Section: Advances In Rna-based Therapies Put Structured Long Noncodin...mentioning

confidence: 99%

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The multiple molecular dimensions of long noncoding RNAs that regulate gene expression and tumorigenesis

Marcia

2022

Current Opinion in Oncology

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Purpose of reviewLncRNAs are emerging as key regulators of gene expression and they ensure homeostasis during cell differentiation and development, replication, and adaptation to the environment. Because of their key central role in regulating the biology of living cells, it is crucial to characterize how lncRNAs function at the genetic, transcriptomic, and mechanistic level. Recent findingsThe low endogenous abundance and high molecular complexity of lncRNAs pose unique challenges for their characterization but new methodological advances in biochemistry, biophysics and cell biology have recently made it possible to characterize an increasing number of these transcripts, including oncogenic and tumor suppressor lncRNAs. These recent studies specifically address important issues that had remained controversial, such as the selectivity of lncRNA mechanisms of action, the functional importance of lncRNA sequences, secondary and tertiary structures, and the specificity of lncRNA interactions with proteins.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Section: Advances In Rna-based Therapies Put Structured Long Noncodin...mentioning

confidence: 99%

The multiple molecular dimensions of long noncoding RNAs that regulate gene expression and tumorigenesis

Marcia

2022

Current Opinion in Oncology

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“…Computer-aided drug design (CADD) has the potential to guide the rational development of small molecules targeting RNA [27,28]. To date, this strategy is hampered by our limited understanding of RNA structural and dynamic properties as well as of the mechanisms of RNA-small molecule (RNA-SM) recognition [14,18].…”

Section: Introductionmentioning

confidence: 99%

HARIBOSS: a curated database of RNA-small molecules structures to aid rational drug design

et al. 2022

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Motivation RNA molecules are implicated in numerous fundamental biological processes and many human pathologies, such as cancer, neurodegenerative disorders, muscular diseases, and bacterial infections. Modulating the mode of action of disease-implicated RNA molecules can lead to the discovery of new therapeutical agents and even address pathologies linked to ‘undruggable’ protein targets. This modulation can be achieved by direct targeting of RNA with small molecules. As of today, only a few RNA-targeting small molecules are used clinically. One of the main obstacles that has hampered the development of a rational drug design protocol to target RNA with small molecules is the lack of a comprehensive understanding of the molecular mechanisms at the basis of RNA-small molecule recognition. Results Here, we present HARIBOSS, a curated collection of RNA-small molecule structures determined by X-ray crystallography, Nuclear Magnetic Resonance spectroscopy and cryo-electron microscopy. HARIBOSS facilitates the exploration of drug-like compounds known to bind RNA, the analysis of ligands and pockets properties, and ultimately the development of in silico strategies to identify RNA-targeting small molecules. Availability HARIBOSS can be explored via a web interface available at http://hariboss.pasteur.cloud. Supplementary information Supplementary data are available at Bioinformatics online.

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“…45–48 However, validation of conventional protein-based docking tools for its applicability against RNA targets is crucial because parameters cannot easily be transferred and nucleic acids hold their own unique challenges different from proteins for docking programmes, like high intrinsic flexibility, negatively charged phosphate backbone which is eventually masked by cations, or a limited chemical diversity. 49–52 Consequently, over the time, some specialized RNA-ligand docking algorithms and scoring functions were developed. 53–62…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, this study demonstrates the general feasibility to perform structure-based virtual screenings against RNA targets, while at the same time it highlights pitfalls and their potential solutions when executing RNA-ligand docking.RNA targets is crucial because parameters cannot easily be transferred and nucleic acids hold their own unique challenges different from proteins for docking programmes, like high intrinsic flexibility, negatively charged phosphate backbone which is eventually masked by cations, or a limited chemical diversity. [49][50][51][52] Consequently, over the time, some specialized RNA-ligand docking algorithms and scoring functions were developed. [53][54][55][56][57][58][59][60][61][62] Once validated against a given dataset to demonstrate the ability to correctly predict crystallographic binding modes (posing) and accurately discriminate binders from non-binders or decoys by scoring, the true challenge for a docking programme is the identification of novel scaffolds for a target by VS.…”

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confidence: 99%

Protein-based Virtual Screening Tools applied for RNA-Ligand Docking identify new Binders of the preQ₁-Riboswitch

Kallert

Fischer

Schneider

et al. 2022

Preprint

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Targeting RNA with small molecules is an emerging field. While several ligands for different RNA targets are reported, structure-based virtual screenings against RNAs are still rare. Here, we elucidated the general capabilities of protein-based docking programmes to reproduce native binding modes of small molecule RNA ligands and to discriminate known binders from decoys by the scoring function. The programmes were found to perform similar compared to the RNA-based docking tool rDOCK and the faced challenges during docking, namely protomer and tautomer selection, target dynamics and explicit solvent, do not largely differ from challenges in conventional protein-ligand docking. A prospective virtual screening with the Bacillus subtilis preQ1-riboswitch aptamer domain performed with FRED, HYBRID and FlexX, followed by microscale thermophoresis assays identified 6 active compounds out of 23 tested virtual screening hits with potencies between 29.5 nM and 11.0 μM. The hits were selected not solely based on their docking score, but for resembling key interactions of the native ligand. Therefore, this study demonstrates the general feasibility to perform structure-based virtual screenings against RNA targets, while at the same time it highlights pitfalls and their potential solutions when executing RNA-ligand docking.

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Computer-aided design of RNA-targeted small molecules: A growing need in drug discovery

Cited by 50 publications

References 159 publications

The multiple molecular dimensions of long noncoding RNAs that regulate gene expression and tumorigenesis

The multiple molecular dimensions of long noncoding RNAs that regulate gene expression and tumorigenesis

HARIBOSS: a curated database of RNA-small molecules structures to aid rational drug design

Protein-based Virtual Screening Tools applied for RNA-Ligand Docking identify new Binders of the preQ₁-Riboswitch

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Computer-aided design of RNA-targeted small molecules: A growing need in drug discovery

Cited by 50 publications

References 159 publications

The multiple molecular dimensions of long noncoding RNAs that regulate gene expression and tumorigenesis

The multiple molecular dimensions of long noncoding RNAs that regulate gene expression and tumorigenesis

HARIBOSS: a curated database of RNA-small molecules structures to aid rational drug design

Protein-based Virtual Screening Tools applied for RNA-Ligand Docking identify new Binders of the preQ1-Riboswitch

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Protein-based Virtual Screening Tools applied for RNA-Ligand Docking identify new Binders of the preQ₁-Riboswitch