Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: Docking between the antimalarial agent and its putative receptor

Shukla, K.; Gund, Tamara; Meshnick, Steven R.

doi:10.1016/0263-7855(94)00001-9

Cited by 48 publications

(31 citation statements)

References 16 publications

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“…In contrast an inactive analogue of artemisinin, deoxyartemisinin, docks in a different manner (51,52). Similar studies with synthetic endoperoxides suggest that docking between an active trioxane and the receptor, heme, is the crucial step for the drug action (53,54).…”

Section: Discussionmentioning

confidence: 64%

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Pandey

Tekwani

Singh

et al. 1999

Journal of Biological Chemistry

225

156

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Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. We found artemisinin to be a potent inhibitor of heme polymerization activity mediated by Plasmodium yoelii lysates as well as Plasmodium falciparum histidine-rich protein II. Interaction of artemisinin with the purified malarial hemozoin in vitro resulted in the concentration-dependent breakdown of the malaria pigment. Our results presented here may explain the selective and rapid toxicity of these drugs on mature, hemozoin-containing, stages of malarial parasite. Since artemisinin and its analogues appear to have similar molecular targets as chloroquine despite having different structures, they can potentially bypass the quinoline resistance machinery of the malarial parasite, which causes sublethal accumulation of these drugs in resistant strains.

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Section: Discussionmentioning

confidence: 64%

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Pandey

Tekwani

Singh

et al. 1999

Journal of Biological Chemistry

225

156

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“…Os resultados mostraram que eles se aproximam do heme preferencialmente por intermédio do átomo de oxigênio O1 da ligação endoperóxido, em direção ao átomo de Fe do receptor heme. Este resultado difere do proposto anteriormente por Shukla e colaboradores 24 , os quais sugeriram que o átomo de oxigênio O2 da artemisinina e não O1 se liga ao ferro do grupo heme. Isto mostra a importância da interação entre o Fe do heme e o grupo endoperóxido da artemisinina ou de seus derivados.…”

Section: Figura 1 Estrutura Do Hemeunclassified

“…Este método difere do estudo feito por Cheng e colaboradores 15 , os quais consideraram a flexibilidade destes grupos, onde ambos os grupos se posicionaram para cima. Por outro lado, Shukla e colaboradores 24 também não consideraram a flexibilidade das cadeias laterais do heme durante a simulação da interação QHS-heme, semelhante ao estudo em questão. Já na artemisinina foram fixados somente quatro átomos: O1, O2 e dois carbonos adjacentes a estes átomos.…”

Section: Figura 3 Visão Do Complexo Artemisinina-heme (áTomos Cinzaunclassified

Estudo teórico da interação existente entre a artemisinina e o heme

Costa¹,

Kiralj²,

Ferreira³

2007

Quím. Nova

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Recebido em 22/8/05; aceito em 25/4/06; publicado na web em 30/8/06 THEORETICAL STUDY OF THE INTERACTION BETWEEN ARTEMISININ AND HEME. The purpose of this work is to study theoretically stereoelectronic aspects of the interaction between heme and artemisinin in the transitional heme-artemisinin complex. Through semi-empirical calculations using the PM3 method, the potential energy barrier of artemisinin rotation relative to heme in the heme-artemisinin complex was studied in vacuum and in the partially solvated state. The minimum heat of formation obtained for the complex with and without water molecules is -702.39 and -100.86 kcal mol -1 , respectively, which corresponds to the dihedral angle CFe-O1-O2 of 43.93º and 51.90º around the iron-oxygen O1 bond, respectively. The water molecules bind to heme via 13 hydrogen . It is observed that the inclusion of water molecules does not affect significantly the stability of the heme-artemisinin complex.Keywords: artemisinin; heme; PM3. INTRODUÇÃODe acordo com a Organização Mundial de Saúde, hoje em dia, a malária é de longe a doença tropical e parasitária que mais causa problemas sociais e econômicos no mundo e só é superada em nú-mero de mortes pela AIDS. A malária ainda é uma das doenças que mais crescem no mundo. O Plasmodium falciparum, responsável pela malária mais grave, afeta severamente a população mundial, causando de 1-1,5 milhões de mortes a cada ano, sendo a maioria crianças de até 5 anos de idade 1 . A malária ocorre principalmente nos países da África, Ásia e América Latina, devido às inadequadas estruturas na área da saúde e baixas condições socioeconômicas.Na . Após a infecção do indiví-duo pela picada do mosquito, os parasitas Plasmodium primeiramente se acumulam nos hepatócitos (células do fígado) na forma de esporozoítos, onde se desenvolvem e tornam-se merozoítos. Em seguida, os merozoítos invadem os eritrócitos para o próximo estágio de sua maturação. Neste estágio os merozoítos desenvolvem-se, tornando-se trofozoítos maduros (forma anelar) e, em seguida, tornamse esquizontes. Após alguns dias, as células vermelhas infectadas arrebentam e os merozoítos são liberados, causando as febres perió-dicas da malária. Cada esquizonte libera de 8-24 merozoítos e estes infectam novos eritrócitos, dando seqüência a um ciclo 4 . Dentro dos eritrócitos o parasita degrada grande parte da hemoglobina, liberando uma porção protéica (globina) e o heme (complexo ferro-porfirina). Em humanos, os parasitas da malária digerem mais de 70% da hemoglobina dentro das células vermelhas infectadas do sangue 5 . Cerca de 30% ou mais desta globina é digerida pelo parasita e usada como fonte de aminoácidos para a síntese de suas próprias proteínas. O heme proveniente da hemoglobina é tóxico para o parasita, que o converte no pigmento malarial. Neste processo, o parasita é destoxificado ao polimerizar o heme, com o auxílio da enzima heme polimerase, produzindo o pigmento da malária (hemozoína) 6 . A Figura 1 mostra a estrutura do heme, onde o átomo de Fe se encontra no estado de ...

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“…CQ binds to FPIX extremely avidly (6), and this saturable CQ uptake into the digestive vacuole has been proposed as the cause of intracellular accumulation of drug by the parasite (3). Artemisinin reacts with FPIX to form an adduct (13,14), and molecular modeling studies have shown that a stable docked configuration of artemisinin and FPIX could exist (15). Bound DHA might sterically protect the CQ from interacting with FPIX, which could cause a decrease in CQ accumulation.…”

mentioning

confidence: 99%

Effects of Piperaquine, Chloroquine, and Amodiaquine on Drug Uptake and of These in Combination with Dihydroartemisinin against Drug-Sensitive and -Resistant Plasmodium falciparum Strains

Fivelman

Adagu

Warhurst

2007

Antimicrob Agents Chemother

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Piperaquine is being developed as a long-acting component in artemisinin combination therapies. It was highly active in vitro and drug interaction studies showed that dihydroartemisinin combinations with piperaquine, chloroquine, and amodiaquine were indifferent tending toward antagonism. Competitive uptake of radiolabeled chloroquine and dihydroartemisinin in combination with other antimalarials was observed.Bis-4-aminoquinoline piperaquine (PPQ) and its analogues have been shown to be potent against chloroquine (CQ)-sensitive (CQS) and CQ-resistant (CQR) parasites in vitro (1,5) and in the field (18). Artemisinin derivatives are being evaluated as combination regimens (ACTs) to treat malaria and in particular to combat multidrug-resistant Plasmodium falciparum. It is hoped that combination chemotherapy will delay or at best prevent the onset of resistance to new agents and avoid cross-resistance to existing ones (20). PPQ has been used successfully for mass prophylaxis and treatment in China (18) and is increasingly being developed as a long-acting component in ACTs (7). One recent study assessed the in vitro interaction between PPQ and dihydroartemisinin (DHA), finding antagonism for K1 (CQR) and no interaction for 3D7 (CQS) strains of P. falciparum (7). An antagonistic drug combination may compromise efficacy and possibly increase the chances of resistance developing and spreading (10), and there may be situations, such as when treatment is incomplete, in which an antagonistic interaction could become significant (7). Our aim was to assess the in vitro effects of DHA in combination with PPQ against a range of P. falciparum strains with various degrees of drug resistance and to compare these results with DHA combined with the common 4-aminoquinolines CQ and amodiaquine (AQ). In addition, we examined the effect of a range of antimalarial drugs on the in vitro uptake of radiolabeled DHA and CQ. Dose-response assays to obtain 50% inhibitory concentration (IC 50 ) values of individual drugs and fixed ratio combination assays were carried out as previously published (10) at 1% parasitemia and 1% hematocrit. Uptake of [ 3 H]DHA (Moravek Biochemicals) at 1.4 Ci/mmol and [ 3 H]CQ (DuPont NEN) at 50.4 Ci/mmol was done at 37°C for 90 min. The experiment was initiated with addition of trophozoite parasites (5% parasitemia, 1.5% hematocrit) to microtubes containing both the unlabeled antimalarial and the radiolabeled drug (12).Samples were then centrifuged through silicon oil (AnalaR; BDH) and processed (12), and the radioactivity was determined on a Beckman liquid scintillation spectrometer. Uptake was represented as a percentage of control parasitized erythrocytes minus the uptake of drug in uninfected erythrocytes (Ϯ the relative standard deviation). All experiments were repeated at least twice in triplicate.The sensitivities of eight laboratory parasite lines were assessed to a range of antimalarial drugs (Table 1). Overall, three of the parasite lines were CQS, four were CQR, and line 106/1 was moderately CQR. CQ IC...

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Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: Docking between the antimalarial agent and its putative receptor

Cited by 48 publications

References 16 publications

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Estudo teórico da interação existente entre a artemisinina e o heme

Effects of Piperaquine, Chloroquine, and Amodiaquine on Drug Uptake and of These in Combination with Dihydroartemisinin against Drug-Sensitive and -Resistant Plasmodium falciparum Strains

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