Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

Autor(es)

Ana Carolina Rennó Sodero ^[1] ; Bárbara Abrahim-Vieira ^[2] ; Pedro Henrique Monteiro Torres ; Pedro Geraldo Pascutti ^[4] ; Célia RS Garcia ^[5] ; Vitor Francisco Ferreira ^[6] ; David Rodrigues da Rocha ^[7] ; Sabrina Baptista Ferreira ^[8] ; Floriano Paes Silva Jr ^[9]

Afiliação do(s) autor(es)

^[1] Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Laboratório de Modelagem Molecular e QSAR - Brasil

^[2] Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Laboratório de Modelagem Molecular e QSAR - Brasil

^[4] Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Modelagem e Dinâmica Molecular - Brasil

^[5] Universidade de São Paulo. Departamento de Fisiologia - Brasil

^[6] Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica - Brasil

^[7] Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica - Brasil

^[8] Universidade Federal do Rio de Janeiro. Instituto de Química. Laboratório de Síntese Orgânica e Prospecção Biológica - Brasil

^[9] Fundação Oswaldo Cruz-Fiocruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos - Brasil

• Tipo de documento: Artigo Científico
• Fonte: Memórias do Instituto Oswaldo Cruz; v. 112, n. 4, p. 299-308, 2017-04-00.

Resumo

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. (AU)

• Processo FAPESP: 11/51295-5 - Genômica funcional em Plasmodium
• Beneficiário: Célia Regina da Silva Garcia
• Modalidade de apoio: Auxílio à Pesquisa - Temático