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Understanding the Mechanism of Atovaquone Drug Resistance in Plasmodium falciparum Cytochrome b Mutation Y268S Using Computational Methods

Please always quote using this URN: urn:nbn:de:bvb:20-opus-114882
  • The rapid appearance of resistant malarial parasites after introduction of atovaquone (ATQ) drug has prompted the search for new drugs as even single point mutations in the active site of Cytochrome b protein can rapidly render ATQ ineffective. The presence of Y268 mutations in the Cytochrome b (Cyt b) protein is previously suggested to be responsible for the ATQ resistance in Plasmodium falciparum (P. falciparum). In this study, we examined the resistance mechanism against ATQ in P. falciparum through computational methods. Here, we reported aThe rapid appearance of resistant malarial parasites after introduction of atovaquone (ATQ) drug has prompted the search for new drugs as even single point mutations in the active site of Cytochrome b protein can rapidly render ATQ ineffective. The presence of Y268 mutations in the Cytochrome b (Cyt b) protein is previously suggested to be responsible for the ATQ resistance in Plasmodium falciparum (P. falciparum). In this study, we examined the resistance mechanism against ATQ in P. falciparum through computational methods. Here, we reported a reliable protein model of Cyt bc1 complex containing Cyt b and the Iron-Sulphur Protein (ISP) of P. falciparum using composite modeling method by combining threading, ab initio modeling and atomic-level structure refinement approaches. The molecular dynamics simulations suggest that Y268S mutation causes ATQ resistance by reducing hydrophobic interactions between Cyt bc1 protein complex and ATQ. Moreover, the important histidine contact of ATQ with the ISP chain is also lost due to Y268S mutation. We noticed the induced mutation alters the arrangement of active site residues in a fashion that enforces ATQ to find its new stable binding site far away from the wild-type binding pocket. The MM-PBSA calculations also shows that the binding affinity of ATQ with Cyt bc1 complex is enough to hold it at this new site that ultimately leads to the ATQ resistance.show moreshow less

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Metadaten
Author: Bashir A. Akhoon, Krishna P. Singh, Megha Varshney, Shishir K. Gupta, Yogeshwar Shukla, Shailendra K. Gupta
URN:urn:nbn:de:bvb:20-opus-114882
Document Type:Journal article
Faculties:Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften
Language:English
Parent Title (English):PLOS ONE
Year of Completion:2014
Volume:9
Issue:10
Pagenumber:e110041
Source:PLoS ONE 9(10): e110041. doi:10.1371/journal.pone.0110041
DOI:https://doi.org/10.1371/journal.pone.0110041
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25334024
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Tag:HIV-1 protease; I-tasser; binding; complex; inhibitors; malaria; molecular-dynamics simulations; protein-protein interactions; saccharomyces cerevisiae; structure prediction
Release Date:2015/07/10
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung