Theoretical Investigation of Repurposed Drugs Potentially Capable of Binding to the Catalytic Site and the Secondary Binding Pocket of Subunit A of Ricin

França, Tanos C. C.; Botelho, Fernanda D.; Drummond, Michael L.; LaPlante, Steven R.

doi:10.1021/acsomega.2c04819

Cited by 5 publications

(3 citation statements)

References 33 publications

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“…The existence of this secondary pocket has been confirmed by the X-ray structure of the RTA-compound complex, indicating that compounds that enter this pocket could induce conformational changes in the primary pocket of active site and affect its activity, leading to antagonism [14,18]. Therefore, it may be essential to target both pockets simultaneously to obtain more effective small-molecule RTA inhibitors [19]. In this study, we discovered a novel compound named RSMI-29 through rational virtual screening, which may target both active pockets of RTA.…”

Section: Introductionmentioning

confidence: 92%

Identification and Biological Evaluation of a Novel Small-Molecule Inhibitor of Ricin Toxin

Yang,

Wei,

Cao

et al. 2024

Molecules

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The plant-derived toxin ricin is classified as a type 2 ribosome-inactivating protein (RIP) and currently lacks effective clinical antidotes. The toxicity of ricin is mainly due to its ricin toxin A chain (RTA), which has become an important target for drug development. Previous studies have identified two essential binding pockets in the active site of RTA, but most existing inhibitors only target one of these pockets. In this study, we used computer-aided virtual screening to identify a compound called RSMI-29, which potentially interacts with both active pockets of RTA. We found that RSMI-29 can directly bind to RTA and effectively attenuate protein synthesis inhibition and rRNA depurination induced by RTA or ricin, thereby inhibiting their cytotoxic effects on cells in vitro. Moreover, RSMI-29 significantly reduced ricin-mediated damage to the liver, spleen, intestine, and lungs in mice, demonstrating its detoxification effect against ricin in vivo. RSMI-29 also exhibited excellent drug-like properties, featuring a typical structural moiety of known sulfonamides and barbiturates. These findings suggest that RSMI-29 is a novel small-molecule inhibitor that specifically targets ricin toxin A chain, providing a potential therapeutic option for ricin intoxication.

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Section: Introductionmentioning

confidence: 92%

Identification and Biological Evaluation of a Novel Small-Molecule Inhibitor of Ricin Toxin

Yang,

Wei,

Cao

et al. 2024

Molecules

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“…As previously described 27 , simulations were performed in triplicate using the AMBER10:EHT 28 force field and NAMD software 29 with a cut-off of 10 kcal/mol for electrostatic interactions and a range between 8 and 10 kcal/mol for van der Waals interactions. The protocol before each production step included 5000 steps of energy minimization followed by 100 ps of isothermal-isobaric ensemble (NPT) simulation and 200 ns of isothermal-isochoric ensemble (NVT).…”

Section: Simulationsmentioning

confidence: 99%

Molecular dynamics of outer membrane-embedded polysaccharide secretion porins reveals closed resting-state surface gates targetable by virtual fragment screening for drug hotspot identification

França,

Saïdi,

Ajamian

et al. 2023

Preprint

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Recent advances in iterative neural-network analyses (e.g. AlphaFold2 and RoseTTA fold) have been revolutionary for protein 3D-structure prediction, especially for difficult-to-manipulate α-helical/β-barrel integral membrane proteins. These model structures are calculated based on the co-evolution of amino acids within the protein of interest and similarities to existing protein structures; local effects of the membrane on folding and stability of the calculated model structures are not considered. We recently reported the discovery, 3D modelling, and characterization of 18-β-stranded outer-membrane (OM) WzpX, WzpS, and WzpB β-barrel secretion porins for the exopolysaccharide (EPS), major spore coat polysaccharide (MASC), and biosurfactant polysaccharide (BPS) pathways (respectively) in the Gram-negative social predatory bacteriumMyxococcus xanthusDZ2. However, information was not obtained regarding the dynamic behavior of surface-gating WzpX/S/B loop domains, nor on potential treatments to inactivate these porins. Herein, we developed a molecular dynamics (MD) protocol to study the core stability and loop dynamism of neural network-based integral membrane protein structure models embedded in an asymmetric OM bilayer, using theM. xanthusWzpX, WzpS, and WzpB proteins as test candidates. This was accomplished through integration of the CHARMM-graphical user interface (GUI) and Molecular Operating Environment (MOE) workflows to allow for rapid simulation system setup and facilitate data analysis. In addition to serving as a method of model-structure validation, our molecular dynamics simulations revealed minimal movement of extracellular WzpX/S/B loops in the absence of an external stimulus, as well as druggable cavities between the loops. Virtual screening of a commercial fragment library against these cavities revealed putative fragment-binding hotspots on the cell-surface face of each β-barrel, along with key interacting residues, and identified promising hits for the design of potential binders capable of plugging the β-barrels and inhibiting polysaccharide secretion.

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“…As the behavior of the PgaA structure was to serve as the reference control, PgaA, as well as WzpX, WzpS, and WzpB, were all inserted in the same simulated OM. Though the LPS structure from M. xanthus is not identical to that of E. coli, 8,25 integral OM proteins from M. xanthus have been repeatedly shown to properly display and interact when heterologously expressed in the E. coli OM, 11,26 indicating a compatible environment.…”

Section: ■ Introductionmentioning

confidence: 99%

Molecular Dynamics of Outer Membrane-Embedded Polysaccharide Secretion Porins Reveals Closed Resting-State Surface Gates Targetable by Virtual Fragment Screening for Drug Hotspot Identification

França,

Saïdi,

Ajamian

et al. 2024

ACS Omega

Self Cite

View full text Add to dashboard Cite

Recent advances in iterative neural network analyses (e.g., AlphaFold2 and RoseTTA fold) have been revolutionary for protein 3D structure prediction, especially for difficult-to-manipulate α-helical/β-barrel integral membrane proteins. These model structures are calculated based on the coevolution of amino acids within the protein of interest and similarities to existing protein structures; the local effects of the membrane on folding and stability of the calculated model structures are not considered. We recently reported the discovery, 3D modeling, and characterization of 18-β-stranded outermembrane (OM) WzpX, WzpS, and WzpB β-barrel secretion porins for the exopolysaccharide (EPS), major spore coat polysaccharide (MASC), and biosurfactant polysaccharide (BPS) pathways (respectively) in the Gram-negative social predatory bacterium Myxococcus xanthus DZ2. However, information was not obtained regarding the dynamic behavior of surface-gating WzpX/S/B loop domains or on potential treatments to inactivate these porins. Herein, we developed a molecular dynamics (MD) protocol to study the core stability and loop dynamism of neural network-based integral membrane protein structure models embedded in an asymmetric OM bilayer, using the M. xanthus WzpX, WzpS, and WzpB proteins as test candidates. This was accomplished through integration of the CHARMM-graphical user interface (GUI) and Molecular Operating Environment (MOE) workflows to allow for a rapid simulation system setup and facilitate data analysis. In addition to serving as a method of model structure validation, our molecular dynamics simulations revealed a minimal movement of extracellular WzpX/S/B loops in the absence of an external stimulus as well as druggable cavities between the loops. Virtual screening of a commercial fragment library against these cavities revealed putative fragment-binding hotspots on the cell-surface face of each β-barrel, along with key interacting residues, and identified promising hits for the design of potential binders capable of plugging the β-barrels and inhibiting polysaccharide secretion.

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Theoretical Investigation of Repurposed Drugs Potentially Capable of Binding to the Catalytic Site and the Secondary Binding Pocket of Subunit A of Ricin

Cited by 5 publications

References 33 publications

Identification and Biological Evaluation of a Novel Small-Molecule Inhibitor of Ricin Toxin

Identification and Biological Evaluation of a Novel Small-Molecule Inhibitor of Ricin Toxin

Molecular dynamics of outer membrane-embedded polysaccharide secretion porins reveals closed resting-state surface gates targetable by virtual fragment screening for drug hotspot identification

Molecular Dynamics of Outer Membrane-Embedded Polysaccharide Secretion Porins Reveals Closed Resting-State Surface Gates Targetable by Virtual Fragment Screening for Drug Hotspot Identification

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