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Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1.

Durrant JD, Hall L, Swift RV, Landon M, Schnaufer A, Amaro RE - PLoS Negl Trop Dis (2010)

Bottom Line: Motivated by the urgent need for novel trypanocidal therapeutics, we use an ensemble-based virtual-screening approach to discover new naphthalene-based TbREL1 inhibitors.Ultimately, four new low-micromolar inhibitors are presented.Three of the four compounds may bind to a newly revealed cleft that represents a putative druggable site not evident in any crystal structure.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT

Background: Neglected tropical diseases, including diseases caused by trypanosomatid parasites such as Trypanosoma brucei, cost tens of millions of disability-adjusted life-years annually. As the current treatments for African trypanosomiasis and other similar infections are limited, new therapeutics are urgently needed. RNA Editing Ligase 1 (REL1), a protein unique to trypanosomes and other kinetoplastids, was identified recently as a potential drug target.

Methodology/principal findings: Motivated by the urgent need for novel trypanocidal therapeutics, we use an ensemble-based virtual-screening approach to discover new naphthalene-based TbREL1 inhibitors. The predicted binding modes of the active compounds are evaluated within the context of the flexible receptor model and combined with computational fragment mapping to determine the most likely binding mechanisms. Ultimately, four new low-micromolar inhibitors are presented. Three of the four compounds may bind to a newly revealed cleft that represents a putative druggable site not evident in any crystal structure.

Conclusions/significance: Pending additional optimization, the compounds presented here may serve as precursors for future novel therapies useful in the fight against several trypanosomatid pathogens, including human African trypanosomiasis, a devastating disease that afflicts the vulnerable patient populations of sub-Saharan Africa.

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Related in: MedlinePlus

Predicted binding of the identified inhibitors to the respective optimal protein conformation from the ensemble.The TbREL1 crystal structure is shown in mesh. The E60 and R111 residues of the optimal conformations are labeled directly, and the E60 residue of the crystal structure is labeled with an arrow. In all four cases, the closed position of the crystal-structure E60 residue would have prevented optimal ligand binding. A) V1. B) V2. C) V3. D) V4.
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pntd-0000803-g003: Predicted binding of the identified inhibitors to the respective optimal protein conformation from the ensemble.The TbREL1 crystal structure is shown in mesh. The E60 and R111 residues of the optimal conformations are labeled directly, and the E60 residue of the crystal structure is labeled with an arrow. In all four cases, the closed position of the crystal-structure E60 residue would have prevented optimal ligand binding. A) V1. B) V2. C) V3. D) V4.

Mentions: In order to investigate why binding to the crystal structure was suboptimal, the crystal structure was compared to the optimal receptor conformation for each of the four ligands. By aligning the best-scoring MD-generated receptor structures to the crystal structure and visualizing both proteins and ligands, it is evident that in all four cases the crystallographic position of E60 prevented optimal binding. During the molecular dynamics simulation, however, E60 extends its contact with R111 (initial contact distance 5.35 Å; final interaction distance greater than 11 Å). This movement opens a wide cleft that is favorably occupied by all four of the novel inhibitors (Figure 3). This unique binding mode, described in more detail below, would not have been identified had protein-receptor flexibility been ignored.


Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1.

Durrant JD, Hall L, Swift RV, Landon M, Schnaufer A, Amaro RE - PLoS Negl Trop Dis (2010)

Predicted binding of the identified inhibitors to the respective optimal protein conformation from the ensemble.The TbREL1 crystal structure is shown in mesh. The E60 and R111 residues of the optimal conformations are labeled directly, and the E60 residue of the crystal structure is labeled with an arrow. In all four cases, the closed position of the crystal-structure E60 residue would have prevented optimal ligand binding. A) V1. B) V2. C) V3. D) V4.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2927429&req=5

pntd-0000803-g003: Predicted binding of the identified inhibitors to the respective optimal protein conformation from the ensemble.The TbREL1 crystal structure is shown in mesh. The E60 and R111 residues of the optimal conformations are labeled directly, and the E60 residue of the crystal structure is labeled with an arrow. In all four cases, the closed position of the crystal-structure E60 residue would have prevented optimal ligand binding. A) V1. B) V2. C) V3. D) V4.
Mentions: In order to investigate why binding to the crystal structure was suboptimal, the crystal structure was compared to the optimal receptor conformation for each of the four ligands. By aligning the best-scoring MD-generated receptor structures to the crystal structure and visualizing both proteins and ligands, it is evident that in all four cases the crystallographic position of E60 prevented optimal binding. During the molecular dynamics simulation, however, E60 extends its contact with R111 (initial contact distance 5.35 Å; final interaction distance greater than 11 Å). This movement opens a wide cleft that is favorably occupied by all four of the novel inhibitors (Figure 3). This unique binding mode, described in more detail below, would not have been identified had protein-receptor flexibility been ignored.

Bottom Line: Motivated by the urgent need for novel trypanocidal therapeutics, we use an ensemble-based virtual-screening approach to discover new naphthalene-based TbREL1 inhibitors.Ultimately, four new low-micromolar inhibitors are presented.Three of the four compounds may bind to a newly revealed cleft that represents a putative druggable site not evident in any crystal structure.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT

Background: Neglected tropical diseases, including diseases caused by trypanosomatid parasites such as Trypanosoma brucei, cost tens of millions of disability-adjusted life-years annually. As the current treatments for African trypanosomiasis and other similar infections are limited, new therapeutics are urgently needed. RNA Editing Ligase 1 (REL1), a protein unique to trypanosomes and other kinetoplastids, was identified recently as a potential drug target.

Methodology/principal findings: Motivated by the urgent need for novel trypanocidal therapeutics, we use an ensemble-based virtual-screening approach to discover new naphthalene-based TbREL1 inhibitors. The predicted binding modes of the active compounds are evaluated within the context of the flexible receptor model and combined with computational fragment mapping to determine the most likely binding mechanisms. Ultimately, four new low-micromolar inhibitors are presented. Three of the four compounds may bind to a newly revealed cleft that represents a putative druggable site not evident in any crystal structure.

Conclusions/significance: Pending additional optimization, the compounds presented here may serve as precursors for future novel therapies useful in the fight against several trypanosomatid pathogens, including human African trypanosomiasis, a devastating disease that afflicts the vulnerable patient populations of sub-Saharan Africa.

Show MeSH
Related in: MedlinePlus