Towards the identification of the binding site of benzimidazoles to β-tubulin of Trichinella spiralis: Insights from computational and experimental data

Aguayo‐Ortiz, Rodrigo; Méndez‐Lucio, Oscar; Medina-Franco, José L.; Castillo, Rafael; Yépez‐Mulia, Lilián; Hernández‐Luis, Francisco; Hernández‐Campos, Alicia

doi:10.1016/j.jmgm.2013.01.007

Cited by 59 publications

(46 citation statements)

References 44 publications

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“…The benzimidazole‐2‐carbamate derivative (BzC) nocodazole (NZ) was identified in this novel binding site interacting with amino acids Asn165, Glu198, and Cys239 . This experimental result validates the binding site of BzCs proposed first by our research group and confirms the importance of amino acids at positions 165, 198, 200, and 239 for the drug stabilization and the partial overlap with the colchicine binding site . Moreover, this structural information also agrees with our suggested mechanisms of parasite resistance and susceptibility to treatment with these BzC drugs, in which we highlighted the importance of β‐tubulin modifications at positions 167, 198, and 200 .…”

Section: Introductionsupporting

confidence: 86%

“…As mentioned before, the NZ binding site was initially proposed by our research group employing molecular modeling strategies . Figure b displays the crystallographic NZ binding mode (PDB ID: 5CA1, orange) superimposed with our previously proposed binding model (green).…”

Section: Resultsmentioning

confidence: 93%

“…The compounds listed in Table were constructed and submitted to a geometry optimization employing the AM1 semi‐empirical method implemented in MOE 2013.08. Series 1 corresponds to the reference BzCs used as antiparasitic drugs: albendazole (ABZ), albendazole sulfoxides (ABZSO+/‐), fenbendazole (FBZ), fenbendazole sulfoxides (FBZSO+/‐), mebendazole (MBZ), NZ, oxibendazole (OBZ), and parbendazole (PBZ). Series 2 and 3 correspond to BzCs synthesized and evaluated as anticancer agents by Guan et al .…”

Section: Methodsmentioning

confidence: 99%

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Structure‐based approaches for the design of benzimidazole‐2‐carbamate derivatives as tubulin polymerization inhibitors

et al. 2017

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Microtubules are highly dynamic assemblies of α/β-tubulin heterodimers whose polymerization inhibition is among one of the most successful approaches for anticancer drug development. Overexpression of the class I (βI) and class III (βIII) β-tubulin isotypes in breast and lung cancers and the highly expressed class VI (βVI) β-tubulin isotype in normal blood cells have increased the interest for designing specific tubulin-binding anticancer therapies. To this end, we employed our previously proposed model of the β-tubulin-nocodazole complex, supported by the recently determined X-ray structure, to identify the fundamental structural differences between β-tubulin isotypes. Moreover, we employed docking and molecular dynamics (MD) simulations to determine the binding mode of a series of benzimidazole-2-carbamete (BzC) derivatives in the βI-, βIII-, and βVI-tubulin isotypes. Our results demonstrate that Ala198 in the βVI isotype reduces the affinity of BzCs, explaining the low bone marrow toxicity for nocodazole. Additionally, no significant differences in the binding modes between βI- and βIII-BzC complexes were observed; however, Ser239 in the βIII isotype might be associated with the low affinity of BzCs to this isotype. Finally, our study provides insight into the β-tubulin-BzC interaction features essential for the development of more selective and less toxic anticancer therapeutics.

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Section: Introductionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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Structure‐based approaches for the design of benzimidazole‐2‐carbamate derivatives as tubulin polymerization inhibitors

et al. 2017

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“…Although the complete crystallographic structure of the beta-tubulin monomer and the mechanism of action of benzimidazoles are still unknown, a recent study used homology modelling techniques along with molecular docking studies to advance this area of research [1]. The study was undertaken on Trichinella spiralis and the researchers were able to suggest a binding site for benzimidazoles that contains several amino acids associated with resistance (Phe-167, Glu-198 and Phe-200).…”

Section: Discussionmentioning

confidence: 99%

Activity of benzimidazoles againstDientamoeba fragilis(Trichomonadida, Monocercomonadidae)in vitroand correlation of beta-tubulin sequences as an indicator of resistance

et al. 2014

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Recently, Dientamoeba fragilis has emerged as a significant and common enteropathogen. The majority of patients with dientamoebiasis present with gastrointestinal complaints and chronic symptoms are common. Numerous studies have successfully demonstrated parasite clearance, coupled with complete resolution of clinical symptoms following treatment with various antiparasitic compounds. Despite this, there is very little in vitro susceptibility data available for the organism. Benzimidazoles are a class of antiparasitic drugs that are commonly used for the treatment of protozoan and helminthic infections. Susceptibility testing was undertaken on four D. fragilis clinical isolates against the following benzimidazoles: albendazole, flubendazole, mebendazole, nocodazole, triclabendazole and thiabendazole. The activities of the antiprotozoal compounds at concentrations ranging from 2 μg/mL to 500 μg/mL were determined via cell counts of D. fragilis grown in xenic culture. All tested drugs showed no efficacy. The beta-tubulin transcript was sequenced from two of the D. fragilis isolates and amino acid sequences predicted a susceptibility to benzimidazoles. This is the first study to report susceptibility profiles for benzimidazoles against D. fragilis, all of which were not active against the organism. This study also found that beta-tubulin sequences cannot be used as a reliable marker for resistance of benzimidazoles in D. fragilis.

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“…Parameters as RMSD, hydrogen bonding and the binding free energy of the complex were analyzed during the molecular dynamics study. Rescoring of the binding free energy was calculated based on the LIE method equation (Aguayo-Ortiz et al, 2013;Aqvist, Medina, & Samuelsson, 1994).…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Insights into the structure and inhibition ofGiardia intestinalisarginine deiminase: homology modeling, docking, and molecular dynamics studies

Trejo-Soto

Aguayo‐Ortiz

Yépez‐Mulia

et al. 2015

Journal of Biomolecular Structure and Dynamics

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Giardia intestinalis arginine deiminase (GiADI) is an important metabolic enzyme involved in the energy production and defense of this protozoan parasite. The lack of this enzyme in the human host makes GiADI an attractive target for drug design against G. intestinalis. One approach in the design of inhibitors of GiADI could be computer-assisted studies of its crystal structure, such as docking; however, the required crystallographic structure of the enzyme still remains unresolved. Because of its relevance, in this work, we present a three-dimensional structure of GiADI obtained from its amino acid sequence using the homology modeling approximation. Furthermore, we present an approximation of the most stable dimeric structure of GiADI identified through molecular dynamics simulation studies. An in silico analysis of druggability using the structure of GiADI was carried out in order to know if it is a good target for design and optimization of selective inhibitors. Potential GiADI inhibitors were identified by docking of a set of 3196 commercial and 19 in-house benzimidazole derivatives, and molecular dynamics simulation studies were used to evaluate the stability of the ligand-enzyme complexes.

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Towards the identification of the binding site of benzimidazoles to β-tubulin of Trichinella spiralis: Insights from computational and experimental data

Cited by 59 publications

References 44 publications

Structure‐based approaches for the design of benzimidazole‐2‐carbamate derivatives as tubulin polymerization inhibitors

Structure‐based approaches for the design of benzimidazole‐2‐carbamate derivatives as tubulin polymerization inhibitors

Activity of benzimidazoles againstDientamoeba fragilis(Trichomonadida, Monocercomonadidae)in vitroand correlation of beta-tubulin sequences as an indicator of resistance

Insights into the structure and inhibition ofGiardia intestinalisarginine deiminase: homology modeling, docking, and molecular dynamics studies

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