Small molecule–RNA recognition: Binding of the benzophenanthridine alkaloids sanguinarine and chelerythrine to single stranded polyribonucleotides

Basu, Pritha; Kumar, Gopinatha Suresh

doi:10.1016/j.jphotobiol.2017.07.022

Cited by 11 publications

(8 citation statements)

References 61 publications

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“…In the context of RNA molecular recognition, these results imply that a conformational selection or induced fit mechanism is valuable for differential recognition of RNA structural motifs by small molecules. 161,192,219 Furthermore, these findings are consistent with previous work suggesting that dynamic RNA structures sample a defined set of available conformations and that these defined sets can be unique for a given RNA structure, thus allowing differentiation. 104,116,161,220 In addition to providing a better understanding of RNA molecular recognition, we evaluated whether the classification power of PRRSM could generate insight into site-specific RNA structure.…”

Section: Pattern Recognition Of Rna By Small Moleculessupporting

confidence: 89%

“…Conversely, a decreased level of differentiation was observed with an increased magnesium concentration, which would be expected to stabilize secondary structure, though an increased level of competition between the magnesium ions and the aminoglycosides for RNA binding cannot be ruled out. , Taken together, this study suggested that conformationally dynamic RNA secondary structures are better differentiated by small molecules. In the context of RNA molecular recognition, these results imply that a conformational selection or induced fit mechanism is valuable for differential recognition of RNA structural motifs by small molecules. ,, Furthermore, these findings are consistent with previous work suggesting that dynamic RNA structures sample a defined set of available conformations and that these defined sets can be unique for a given RNA structure, thus allowing differentiation. ,,, …”

Section: Structural and Dynamics Considerations For Rna Recognitionsupporting

confidence: 88%

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RNA Structural Differentiation: Opportunities with Pattern Recognition

Eubanks

Hargrove

2018

Biochemistry

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Our awareness and appreciation of the many regulatory roles of RNA have dramatically increased in the past decade. This understanding, in addition to the impact of RNA in many disease states, has renewed interest in developing selective RNA-targeted small molecule probes. However, the fundamental guiding principles in RNA molecular recognition that could accelerate these efforts remain elusive. While high-resolution structural characterization can provide invaluable insight, examples of well-characterized RNA structures, not to mention small molecule:RNA complexes, remain limited. This Perspective provides an overview of the current techniques used to understand RNA molecular recognition when high-resolution structural information is unavailable. We will place particular emphasis on a new method, pattern recognition of RNA with small molecules (PRRSM), that provides rapid insight into critical components of RNA recognition and differentiation by small molecules as well as into RNA structural features.

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Section: Pattern Recognition Of Rna By Small Moleculessupporting

confidence: 89%

Section: Structural and Dynamics Considerations For Rna Recognitionsupporting

confidence: 88%

RNA Structural Differentiation: Opportunities with Pattern Recognition

Eubanks

Hargrove

2018

Biochemistry

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“…Select compounds for which calorimetric studies were reported by Suresh Kumar and coworkers as well as Patino and co-workers. 79,[89][90][91][92] Schematic illustration of techniques discussed herein. (a) Comparison between ITC and DSC.…”

Section: Discussionmentioning

confidence: 99%

“…In a study of benzophenanthridine alkaloids sanguinarine and chelerythrine (Figure 4) binding to single-stranded poly(I), poly(G), and poly(C), Suresh Kumar and Basu showed that the energetics of a small molecule's binding to homopolymeric RNAs can differ on the basis of the RNA sequence. 92 While all interactions with sanguinarine were enthalpy-driven, interactions with chelerythrine were enthalpydriven for poly(I) and entropy-driven for poly(C), and the two energetic terms were comparable for poly(G). This observation showed that the limited chemical diversity of nucleobases is not necessarily an impediment to RNA ligand development; the homopolymeric RNAs were different enough to lead to different thermodynamic profiles with the same ligand.…”

Section: Acs Chemical Biologymentioning

confidence: 97%

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Understanding the Contributions of Conformational Changes, Thermodynamics, and Kinetics of RNA–Small Molecule Interactions

Juru

Hargrove

2019

ACS Chem. Biol.

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The implication of RNA in multiple cellular processes beyond protein coding has revitalized interest in the development of small molecules for therapeutically targeting RNA and for further probing its cellular biology. However, the process of rationally designing such small molecule probes is hampered by the paucity of information about fundamental molecular recognition principles of RNA. In this Review, we summarize two important and often underappreciated aspects of RNA-small molecule recognition: RNA conformational dynamics and the biophysical properties of interactions of small molecules with RNA, specifically thermodynamics and kinetics. While conformational flexibility is often said to impede RNA ligand development, the ability of small molecules to influence the RNA conformational landscape can have a significant effect on the cellular functions of RNA. An analysis of the conformational landscape of RNA and the interactions of individual conformations with ligands can thus guide the development of new small molecule probes, which needs to be investigated further. Additionally, while it is common practice to quantify the binding affinities (K a or K d) of small molecules for biomacromolecules as a measure of their activity, further biophysical characterization of their interaction can provide a deeper understanding. Studies that focus on the thermodynamic and kinetic parameters for interaction between RNA and ligands are next discussed. Finally, this Review provides the reader with a perspective on how such in-depth analysis of biophysical characteristics of the interaction of RNA and small molecules can impact our understanding of these interactions and how they will benefit the future design of small molecule probes.

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Interaction of the putative anticancer alkaloid chelerythrine with nucleic acids: biophysical perspectives

Basu

Kumar

2020

Biophys Rev

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Alkaloids represent an important group of molecules that have immense pharmacological potential. Benzophenanthridine alkaloids are one such class of alkaloids known for their myriad pharmacological activities that include potential anticancer activities. Chelerythrine is a premier member of the benzophenanthridine family of the isoquinoline group. This alkaloid is endowed with excellent medicinal properties and exhibits antibacterial, antimicrobial and anti-inflammatory properties. The molecular basis of its therapeutic activity is considered due to its nucleic acid binding capabilities. This review focuses on consolidating the current status on the nucleic acid binding properties of chelerythrine that is essential for the rational design and development of this alkaloid as a potential drug. This work reviews the interaction of chelerythrine with different natural and synthetic nucleic acids like double-and single-stranded DNAs, heat-denatured DNA, quadruplex DNA, double-and single-stranded RNA, tRNA and triplex and quadruplex RNA. The review emphasizes on the mode, specificity, conformational aspects and energetics of the binding that is particularly helpful for developing nucleic acid targeted therapeutics. The fundamental results discussed in this review will greatly benefit drug development for many diseases and serve as a database for the design of futuristic benzophenanthridine-based therapeutics.

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Small molecule–RNA recognition: Binding of the benzophenanthridine alkaloids sanguinarine and chelerythrine to single stranded polyribonucleotides

Cited by 11 publications

References 61 publications

RNA Structural Differentiation: Opportunities with Pattern Recognition

RNA Structural Differentiation: Opportunities with Pattern Recognition

Understanding the Contributions of Conformational Changes, Thermodynamics, and Kinetics of RNA–Small Molecule Interactions

Interaction of the putative anticancer alkaloid chelerythrine with nucleic acids: biophysical perspectives

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