Molecular docking studies of filarial β-tubulin protein models with antifilarial phytochemicals

Halder, Sumit T; Dhorajiwala, Tehseen M; Samant, Lalit R.

doi:10.4103/bbrj.bbrj_100_19

Cited by 11 publications

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“…Benzimidazole drugs bind to b-tubulin proteins and disrupt the microtubule function (23). Thus, mutations in the b-tubulin gene family can alter the amino acid sequence of the b-tubulin protein, making the b-tubulin protein less sensitive to benzimidazoles (32). Which in turn makes the parasite resistant to the drug.…”

Section: Main Outcomementioning

confidence: 99%

“…The b-tubulin gene families of many helminths, such as Trichinella spiralis, filarial nematodes and H. contortus, have been used to perform in silico docking studies (32,34).These studies noted the protein conformational changes that take place when resistance mutations are present and their effects on drug interactions (32)(33)(34). Presently, little work has been done to apply these methods to A. lumbricoides, and few studies have done research into the changes that may possibly occur between the individual b-tubulin isotypes within a genus or species by detecting the frequency of the F200Y, F167Y and E198A SNPs (20-27).…”

Section: Main Outcomementioning

confidence: 99%

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Single nucleotide polymorphisms in the β-tubulin gene family of Ascaris lumbricoides and their potential role in benzimidazole resistance: a systematic review

Ramkhelawan,

Naidoo,

Mkhize-Kwitshana

2024

Front. Trop. Dis

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IntroductionThe most common soil-transmitted helminthic infection is caused by Ascaris lumbricoides (A. lumbricoides). Approximately 4 billion people are at risk of infection globally. The World Health Organisation recommends the administration of benzimidazole- containing deworming drugs (Albendazole and Mebendazole) to all susceptible populations. Due to this high drug pressure, these parasites may develop resistance to current benzimidazole drugs. The β-tubulin gene family is the target gene for benzimidazole deworming drugs. This systematic review aimed to highlight work that explored the genetic mutations in the β-tubulin gene family of A. lumbricoides that are associated with potential benzimidazole resistance.MethodsAn electronic search of several online databases was used to extract eligible articles using specific keywords related to the topic of interest.ResultsThe majority of ascariasis infections occur in the subtropical and tropical regions of sub-Saharan Africa, the Americas and East Asia, although not enough studies were done to extensively cover this geographical range. In the β-tubulin gene family of A. lumbricoides the mutations at codons F200Y (TTC/Phenylalanine to TAC/Tyrosine), E198A (GAG, GAA/Glutamic acid to GCG, GCA/Alanine) and F167Y (TTC, TTT/Phenylalanine to TAC, TAT/Tyrosine) were associated with potential benzimidazole resistance.DiscussionResistant mutations were found in A. lumbricoides samples at codon F167Y from Haiti, Kenya and Panama. The first evidence of the mutation at codon F200Y was observed in Brazil. The codon E198A mutation was the least prevalent and most undetected.ConclusionThere is a serious shortage of studies investigating the prevalence of β-tubulin gene family mutations in A. lumbricoides populations from endemic areas; this is a serious concern as resistance will negatively impact current mass drug administration programmes.

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Section: Main Outcomementioning

confidence: 99%

Section: Main Outcomementioning

confidence: 99%

Single nucleotide polymorphisms in the β-tubulin gene family of Ascaris lumbricoides and their potential role in benzimidazole resistance: a systematic review

Ramkhelawan,

Naidoo,

Mkhize-Kwitshana

2024

Front. Trop. Dis

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Functional amyloid of extracellular polymeric substances of marine bacterium Pseudomonas aeruginosa PFL-P1 in the binding of polycyclic aromatic hydrocarbons

Kumari

Gupta

Das

2023

Process Biochemistry

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Identification of key interactions of benzimidazole resistance-associated amino acid mutations in Ascaris β-tubulins by molecular docking simulations

Jones

Vliet

LaCourse

et al. 2022

Sci Rep

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Ascaris species are soil-transmitted helminths that infect humans and livestock mainly in low and middle-income countries. Benzimidazole (BZ) class drugs have predominated for many years in the treatment of Ascaris infections, but persistent use of BZs has already led to widespread resistance in other nematodes, and treatment failure is emerging for Ascaris. Benzimidazoles act by binding to β-tubulin proteins and destabilising microtubules. Three mutations in the β-tubulin protein family are associated with BZ resistance. Seven shared β-tubulin isotypes were identified in Ascaris lumbricoides and A. suum genomes. Benzimidazoles were predicted to bind to all β-tubulin isotypes using in silico docking, demonstrating that the selectivity of BZs to interact with one or two β-tubulin isotypes is likely the result of isotype expression levels affecting the frequency of interaction. Ascaris β-tubulin isotype A clusters with helminth β-tubulins previously shown to interact with BZ. Molecular dynamics simulations using β-tubulin isotype A highlighted the key role of amino acid E198 in BZ-β-tubulin interactions. Simulations indicated that mutations at amino acids E198A and F200Y alter binding of BZ, whereas there was no obvious effect of the F167Y mutation. In conclusion, the key interactions vital for BZ binding with β-tubulins have been identified and show how mutations can lead to resistance in nematodes.

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Molecular docking studies of filarial β-tubulin protein models with antifilarial phytochemicals

Cited by 11 publications

References 0 publications

Single nucleotide polymorphisms in the β-tubulin gene family of Ascaris lumbricoides and their potential role in benzimidazole resistance: a systematic review

Single nucleotide polymorphisms in the β-tubulin gene family of Ascaris lumbricoides and their potential role in benzimidazole resistance: a systematic review

Functional amyloid of extracellular polymeric substances of marine bacterium Pseudomonas aeruginosa PFL-P1 in the binding of polycyclic aromatic hydrocarbons

Identification of key interactions of benzimidazole resistance-associated amino acid mutations in Ascaris β-tubulins by molecular docking simulations

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