Probing Riboswitch Binding Sites with Molecular Docking, Focused Libraries, and In-line Probing Assays

Colizzi, Francesco; Lamontagne, Anne-Marie; Lafontaine, Daniel A.; Bussi, Giovanni

doi:10.1007/978-1-62703-730-3_11

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…While various SBVS algorithms, originally developed for protein targets, can be applied to RNA targets, their application requires RNA specific re-parameterization of scoring function or the development of RNA-specific approaches. Towards this end, our group and others have made some advancements and discovered novel ligands against purine, SAM and lysine riboswitches [ 123 , 124 , 125 , 126 ]. The developments in RNA-targeted virtual screening are discussed in detail elsewhere [ 121 , 127 ].…”

Section: General Considerations For Riboswitch Drug Discoverymentioning

confidence: 99%

Riboswitches as Drug Targets for Antibiotics

Panchal

Brenk

2021

Antibiotics

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Riboswitches reside in the untranslated region of RNA and regulate genes involved in the biosynthesis of essential metabolites through binding of small molecules. Since their discovery at the beginning of this century, riboswitches have been regarded as potential antibacterial targets. Using fragment screening, high-throughput screening and rational ligand design guided by X-ray crystallography, lead compounds against various riboswitches have been identified. Here, we review the current status and suitability of the thiamine pyrophosphate (TPP), flavin mononucleotide (FMN), glmS, guanine, and other riboswitches as antibacterial targets and discuss them in a biological context. Further, we highlight challenges in riboswitch drug discovery and emphasis the need to develop riboswitch specific high-throughput screening methods.

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Section: General Considerations For Riboswitch Drug Discoverymentioning

confidence: 99%

Riboswitches as Drug Targets for Antibiotics

Panchal

Brenk

2021

Antibiotics

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“…Therefore, in general the methods developed for proteins can also be applied for RNA [20,27,[48][49][50]. However, there are several challenges which have to be considered when transferring the methods.…”

Section: Rna-ligand Dockingmentioning

confidence: 99%

Structure-Based Discovery of Small Molecules Binding to RNA

Wehler

Brenk

2017

Topics in Medicinal Chemistry

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Ribonucleic acids (RNAs) constitute attractive drug targets. The wealth of structural information about RNAs is steadily increasing making it possible to use this information for the design of new ligands. Two methods that make heavy use of structural knowledge for ligand discovery are molecular docking and fragment screening. In molecular docking the structure of the binding site is used as a template for the design of new ligands using computational methods whereas in fragment screening biophysical methods are used for the detection of weak binding ligands which are subsequently elaborated into tighter binding molecules. In this chapter, we give an overview of both methods in the context of ligand discovery for RNA targets and illustrate their applications for hit discovery.

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“…From a synthesis viewpoint this approach is interesting, certainly feasible as modern organic chemistry equips researchers with powerful tools to design and synthesize diverse sets of compounds. Lafontaine and co-workers used molecular docking to screen a virtual library, actually finding PC1 binding to the xpt guanine riboswitch, which can be performed nowadays with online tools . This approach is yet underrepresented in possible compound design recognizing riboswitches probably because it is hard to foresee which artificial modifications will be tolerated or even engaged by the RNA.…”

Section: A Chemist’s Perspective On Riboswitch Ligand Drug Designmentioning

confidence: 99%

“…Lafontaine and co-workers used molecular docking to screen a virtual library, actually finding PC1 binding to the xpt guanine riboswitch, which can be performed nowadays with online tools. 97 This approach is yet underrepresented in possible compound design recognizing riboswitches probably because it is hard to foresee which artificial modifications will be tolerated or even engaged by the RNA. Thus, Chen et al synthesized a comprehensive library of thiamine pyrophosphate analogues from which they identified the triazole-containing analogue of TPP as potent TPP riboswitch activator in vitro.…”

Section: Dissimilarity Of Artificial Riboswitch Ligandsmentioning

confidence: 99%

(Dis)similar Analogues of Riboswitch Metabolites as Antibacterial Lead Compounds

Matzner

Mayer

2015

J. Med. Chem.

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The rise of antimicrobial resistance in human pathogenic bacteria has increased the necessity for the discovery of novel, yet unexplored antibacterial drug targets. Riboswitches, which are embedded in untranslated regions of bacterial messenger RNA (mRNA), represent such an interesting target structure. These RNA elements regulate gene expression upon binding to natural metabolites, second messengers, and inorganic ions, such as fluoride with high affinity and in a highly discriminative manner. Recently, efforts have been directed toward the identification of artificial riboswitch activators by establishing high-throughput screening assays, fragment-based screening, and structure-guided ligand design approaches. Emphasis in this review is placed on the special requirements and synthesis of new potential antibiotic drugs that target riboswitches in which dissimilarity is an important aspect in the design of potential lead compounds.

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Probing Riboswitch Binding Sites with Molecular Docking, Focused Libraries, and In-line Probing Assays

Cited by 7 publications

References 29 publications

Riboswitches as Drug Targets for Antibiotics

Riboswitches as Drug Targets for Antibiotics

Structure-Based Discovery of Small Molecules Binding to RNA

(Dis)similar Analogues of Riboswitch Metabolites as Antibacterial Lead Compounds

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