RNA: Opening New Doors in Medicinal Chemistry, a Special Issue

Garner, Amanda L.; Djurić, Stevan W.

doi:10.1021/acsmedchemlett.1c00279

Cited by 3 publications

(2 citation statements)

References 52 publications

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“… 36 It has been recently pointed out that several therapies based on small molecules or oligonucleotides present the general aim of targeting RNA biology. 37 RNase A has been also frequently used as a model protein in metalation studies, and structures with several metallodrugs, 38 , 39 including cisplatin, carboplatin, oxaliplatin, 40 and Ru-, 41 Rh-, 42 Pd-, 43 Ir-, 44 and Au-based drugs, 45 are known. Recently, the metalation of arsenoplatin-1, a dual pharmacophore anticancer agent, has been presented.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the V^IVO–Picolinato Complex with RNase A

et al. 2021

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The structure, stability, and enzymatic activity of the adduct formed upon the reaction of the V–picolinato (pic) complex [V IV O(pic) 2 (H 2 O)], with an octahedral geometry and the water ligand in cis to the V=O group, with the bovine pancreatic ribonuclease (RNase A) were studied. While electrospray ionization-mass spectrometry, circular dichroism, and ultraviolet–visible absorption spectroscopy substantiate the interaction between the metal moiety and RNase A, electron paramagnetic resonance (EPR) allows us to determine that a carboxylate group, stemming from Asp or Glu residues, and imidazole nitrogen from His residues are involved in the V binding at acidic and physiological pH, respectively. Crystallographic data demonstrate that the V IV O(pic) 2 moiety coordinates the side chain of Glu111 of RNase A, by substituting the equatorial water molecule at acidic pH. Computational methods confirm that Glu111 is the most affine residue and interacts favorably with the OC -6-23-Δ enantiomer establishing an extended network of hydrogen bonds and van der Waals stabilizations. By increasing the pH around neutrality, with the deprotonation of histidine side chains, the binding of the V complex to His105 and His119 could occur, with that to His105 which should be preferred when compared to that to the catalytically important His119. The binding of the V compound affects the enzymatic activity of RNase A, but it does not alter its overall structure and stability.

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Section: Introductionmentioning

confidence: 99%

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the V^IVO–Picolinato Complex with RNase A

et al. 2021

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“…Also, the discovery of riboswitch targeting drug-like molecule (ribocil) with antibacterial activity against bacteria harboring the FMN riboswitch provides further support that identifying RNA-targeting some molecules is a viable drug development strategy. 6 Further, the identification of antifungal molecules (by Pyle and coworkers) that target the highly structured group II intron and inhibit splicing, 7 along with other recent discoveries, [8][9][10][11][12] provides additional validation of the viability of RNAs, particularly highly structured RNAs, as drug targets.…”

Section: Introductionmentioning

confidence: 99%

AI-Generated Virtual Libraries Could Help Uncover RNA-Specific Regions of Chemical Space

Frank

2022

Preprint

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RNAs can recognize small-molecule ligands. However, the extent to which the molecules that they recognize differ from those recognized by proteins remains an open question. Cheminformatics analysis of experimentally validated RNA binders strongly suggests that RNA binders occupy a specific region of chemical space. However, less than 100 validated small molecule ligands are currently known. Here, we demonstrate how structure-based approaches could be used to navigate vast regions of the chemical space specific to ligand binding sites in five highly-structured RNAs. Our method involves using generative-AI to design target- and site-specific virtual libraries and then analyzing them using similar cheminformatics approaches as those used to assess experimentally validated RNA binders. Despite employing a completely orthogonal strategy, our results essentially reproduce the trends observed by analyzing the experimentally validated RNA binders. Large-scale generation of target and site-specific libraries may therefore prove to be helpful in simultaneously mapping the regions of chemical space unique to RNA and generating libraries that could be mined to identify novel RNA binders.

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In silico investigation of organometallic complexes for identification of RNase A inhibitor

Sepay¹,

Mandal²,

Chakraborty³

2023

Journal of Organometallic Chemistry

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RNA: Opening New Doors in Medicinal Chemistry, a Special Issue

Cited by 3 publications

References 52 publications

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the V^IVO–Picolinato Complex with RNase A

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the V^IVO–Picolinato Complex with RNase A

AI-Generated Virtual Libraries Could Help Uncover RNA-Specific Regions of Chemical Space

In silico investigation of organometallic complexes for identification of RNase A inhibitor

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RNA: Opening New Doors in Medicinal Chemistry, a Special Issue

Cited by 3 publications

References 52 publications

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the VIVO–Picolinato Complex with RNase A

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the VIVO–Picolinato Complex with RNase A

AI-Generated Virtual Libraries Could Help Uncover RNA-Specific Regions of Chemical Space

In silico investigation of organometallic complexes for identification of RNase A inhibitor

Contact Info

Product

Resources

About

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the V^IVO–Picolinato Complex with RNase A

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the V^IVO–Picolinato Complex with RNase A