Sulfur incorporation generally improves Ricin inhibition in pterin-appended glycine-phenylalanine dipeptide mimics

Wiget, Paul A.; Manzano, L.A.; Pruet, Jeff M.; Gao, Guang; Saito, Ryota; Monzingo, A.F.; Jasheway, K.R.; Robertus, Jon D.; Anslyn, Eric V.

doi:10.1016/j.bmcl.2013.10.017

Cited by 17 publications

(12 citation statements)

References 39 publications

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“…Regarding Ligand 5, this is not unexpected since this ligand has a guanine ring, the very same nitrogenous base of rRNA that binds preferentially to the RTA secondary site. An analogous argument applies for Ligand 4, which showed little or no interactions with secondary site residues: this ligand has a pterin ring that is also present in the reference molecule NNPT ( Figure 2) and is known to behave similarly to an adenine ring [14][15][16]30], the natural substrate of RTA inside the cell. Hence, although Ligand 4 appears to be long enough to bind residues of both pockets according to the docking studies, its high affinity for the active site contributes for the occupation of this site only and this is probably the reason why it interacted mainly with residues of the active site.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 81%

“…Similar computational methodologies have been applied before and proven to lead to promising experimental results [18][19][20][21]. We postulated that a ligand that is capable of simultaneously stablishing H-bonds with residues of the active site and of the secondary site of RTA is more likely to show satisfactory inhibitory activity than the current inhibitors that were already shown to occupy solely the active site [14][15][16]. Thus, our ligand selection was primarily based on the analysis of H-bonds formed between the ligand and residues of the active and secondary sites of RTA.…”

Section: Introductionmentioning

confidence: 84%

“…is more likely to show satisfactory inhibitory activity than the current inhibitors that were already shown to occupy solely the active site [14][15][16]. Thus, our ligand selection was primarily based on the analysis of H-bonds formed between the ligand and residues of the active and secondary sites of RTA.…”

Section: Protein Preparation and Redocking Proceduresmentioning

confidence: 99%

“…The competitive RTA inhibitors currently reported in literature are able to inhibit it only at the micromolar range [14][15][16]. This suggests that there is still room for the search of compounds capable of achieving the nanomolar range necessary for an effective inhibition and consequent neutralization of the RTA action inside the cell.…”

Section: Introductionmentioning

confidence: 99%

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Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Botelho

Santos

Gonçalves³

et al. 2020

Toxins

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Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.

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Section: Molecular Dynamics Simulationsmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 84%

Section: Protein Preparation and Redocking Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Botelho

Santos

Gonçalves³

et al. 2020

Toxins

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show abstract

“…By deprotonation of the lactam NH, and conversion to the DBU salt, the pterin easily dissolves in methanol at high concentrations, unprecedented for unfunctionalized pterins. This greatly accelerated the development of a library of bioactive pterins, as it bypassed the problematic insolubility and assisted in derivatization [14][15][16]. In addition to this improvement in solubility, we can further take advantage of a mechanistic role of DBU, as it catalyzes the ester-to-amide transformation, allowing for 7-methoxycarbonylpterin (7-CMP, 1) to smoothly generate new pterin amides ( Figure 1) [14,17].…”

Section: Introductionmentioning

confidence: 99%

Exploring the scope of DBU-promoted amidations of 7-methoxycarbonylpterin

Bockman

Pruet

2020

Beilstein J. Org. Chem.

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The synthetic utility of pterins is often hampered by the notorious insolubility of this heterocycle, slowing the development of medicinally relevant pteridine derivatives. Reactions which expedite the development of new pterins are thus of great importance. Through a dual role of diazabicycloundecene (DBU), 7-carboxymethylpterin is converted to the soluble DBU salt, with additional DBU promoting an ester-to-amide transformation. We have explored this reaction to assess its scope and identify structural features in the amines which significantly affect success, monitored the reaction kinetics using a pseudo-first order kinetics model, and further adapted the reaction conditions to allow for product formation in as little as 5 min, with yields often >80%.

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Endothioxopeptides: A conformational overview

et al. 2016

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Although thionamides would have been first prepared two centuries ago and their chemical and spectroscopic properties extensively investigated, only much more recently (since about 1985) a well deserved but still insufficient attention has been paid to their endothioxopeptide subfamily which nonetheless currently represents a rapidly emerging area of great scientific interest in the broader field of foldameric compounds based on biologically relevant building blocks. After two brief sections offering information on the unfortunately still limited number of endothioxopeptides discovered from natural sources but also on the impressive advancements registered in the last few years in their synthetic methods, this review article outlines the results of a detailed literature survey on the ongoing great, but not systematic, progress related to the conformational consequences generated by incorporating one (or more) thionamide group(s) into a polypeptide chain. Finally, a short discussion of the growing, but still in its infancy, class of the endoselenoxopeptide congeners is also presented.

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Sulfur incorporation generally improves Ricin inhibition in pterin-appended glycine-phenylalanine dipeptide mimics

Cited by 17 publications

References 39 publications

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Exploring the scope of DBU-promoted amidations of 7-methoxycarbonylpterin

Endothioxopeptides: A conformational overview

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