Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling
BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.
Main Authors: | , , , , , , , , |
---|---|
Format: | Digital revista |
Language: | English |
Published: |
Instituto Oswaldo Cruz, Ministério da Saúde
2017
|
Online Access: | http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762017000400299 |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
id |
oai:scielo:S0074-02762017000400299 |
---|---|
record_format |
ojs |
spelling |
oai:scielo:S0074-027620170004002992017-03-13Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modellingSodero,Ana Carolina RennóAbrahim-Vieira,BárbaraTorres,Pedro Henrique MonteiroPascutti,Pedro GeraldoGarcia,Célia RSFerreira,Vitor FranciscoRocha,David Rodrigues daFerreira,Sabrina BaptistaSilva Jr,Floriano Paes atovaquone Plasmodium falciparum molecular docking surflex-dock AutoDock4.2 BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.info:eu-repo/semantics/openAccessInstituto Oswaldo Cruz, Ministério da SaúdeMemórias do Instituto Oswaldo Cruz v.112 n.4 20172017-04-01info:eu-repo/semantics/articletext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762017000400299en10.1590/0074-02760160417 |
institution |
SCIELO |
collection |
OJS |
country |
Brasil |
countrycode |
BR |
component |
Revista |
access |
En linea |
databasecode |
rev-scielo-br |
tag |
revista |
region |
America del Sur |
libraryname |
SciELO |
language |
English |
format |
Digital |
author |
Sodero,Ana Carolina Rennó Abrahim-Vieira,Bárbara Torres,Pedro Henrique Monteiro Pascutti,Pedro Geraldo Garcia,Célia RS Ferreira,Vitor Francisco Rocha,David Rodrigues da Ferreira,Sabrina Baptista Silva Jr,Floriano Paes |
spellingShingle |
Sodero,Ana Carolina Rennó Abrahim-Vieira,Bárbara Torres,Pedro Henrique Monteiro Pascutti,Pedro Geraldo Garcia,Célia RS Ferreira,Vitor Francisco Rocha,David Rodrigues da Ferreira,Sabrina Baptista Silva Jr,Floriano Paes Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling |
author_facet |
Sodero,Ana Carolina Rennó Abrahim-Vieira,Bárbara Torres,Pedro Henrique Monteiro Pascutti,Pedro Geraldo Garcia,Célia RS Ferreira,Vitor Francisco Rocha,David Rodrigues da Ferreira,Sabrina Baptista Silva Jr,Floriano Paes |
author_sort |
Sodero,Ana Carolina Rennó |
title |
Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling |
title_short |
Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling |
title_full |
Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling |
title_fullStr |
Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling |
title_full_unstemmed |
Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling |
title_sort |
insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling |
description |
BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite. |
publisher |
Instituto Oswaldo Cruz, Ministério da Saúde |
publishDate |
2017 |
url |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762017000400299 |
work_keys_str_mv |
AT soderoanacarolinarenno insightsintocytochromebc1complexbindingmodeofantimalarial2hydroxy14naphthoquinonesthroughmolecularmodelling AT abrahimvieirabarbara insightsintocytochromebc1complexbindingmodeofantimalarial2hydroxy14naphthoquinonesthroughmolecularmodelling AT torrespedrohenriquemonteiro insightsintocytochromebc1complexbindingmodeofantimalarial2hydroxy14naphthoquinonesthroughmolecularmodelling AT pascuttipedrogeraldo insightsintocytochromebc1complexbindingmodeofantimalarial2hydroxy14naphthoquinonesthroughmolecularmodelling AT garciaceliars insightsintocytochromebc1complexbindingmodeofantimalarial2hydroxy14naphthoquinonesthroughmolecularmodelling AT ferreiravitorfrancisco insightsintocytochromebc1complexbindingmodeofantimalarial2hydroxy14naphthoquinonesthroughmolecularmodelling AT rochadavidrodriguesda insightsintocytochromebc1complexbindingmodeofantimalarial2hydroxy14naphthoquinonesthroughmolecularmodelling AT ferreirasabrinabaptista insightsintocytochromebc1complexbindingmodeofantimalarial2hydroxy14naphthoquinonesthroughmolecularmodelling AT silvajrflorianopaes insightsintocytochromebc1complexbindingmodeofantimalarial2hydroxy14naphthoquinonesthroughmolecularmodelling |
_version_ |
1756383863965220864 |