Computational insights into the inhibition of hemozoin formation by antimalarial gold(I) hybrids acting by binding free ferriheme

IF 2.8 4区化学 Q3 CHEMISTRY, INORGANIC & NUCLEAR

Transition Metal Chemistry Pub Date : 2025-09-12 DOI:10.1007/s11243-025-00684-0

G. Y. Sánchez Delgado, Frederico Henrique do C. Ferreira, Luiz Antônio S. Costa, Maribel Navarro

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引用次数: 0

Abstract

Malaria remains a global health challenge due to the emergence and spread of drug-resistant strains, highlighting the urgent need for the development of new treatments. Gold(I) hybrids, [AuCQPQ]⁺ (Auhyb1) and [AuAQPQ]⁺ (Auhyb2), incorporating chloroquine (CQ), amodiaquine (AQ), and primaquine (PQ), exhibited potent antiplasmodial activity by disrupting hemozoin formation, likely through ferriheme binding. To elucidate these interactions, we employed molecular dynamics and DFT calculations to assess binding conformations and energies. Results indicate that protonated Auhyb1 forms a clamp-type structure around ferriheme, stabilizing the formed complex via strong H-bonds and π–π stacking. Such interactions reflect a decrease in enthalpy, while the gold ion presence induces an entropy effect also favoring the association with ferriheme. Auhyb2, in contrast, interacts through AQ’s alcohol group coordination to iron, alongside H-bonding and π–π interactions, forming a stable alkoxide metal complex. These molecular interactions could enhance the antimalarial efficacy of conventional low-cost aminoquinoline drugs contributing to disrupt hemozoin crystallization in malaria’s parasite.

Graphical abstract

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通过结合自由铁血红素，抗疟金(I)杂合体抑制血色素形成的计算见解

由于耐药菌株的出现和传播，疟疾仍然是一项全球卫生挑战，这突出表明迫切需要开发新的治疗方法。金(I)杂种，[AuCQPQ]+ (Auhyb1)和[AuAQPQ]+ (Auhyb2)，结合氯喹（CQ）、阿莫地喹（AQ）和伯氨喹（PQ），表现出有效的抗疟原虫活性，可能是通过铁血红素结合破坏血色素的形成。为了阐明这些相互作用，我们采用分子动力学和DFT计算来评估结合构象和能量。结果表明，质子化后的Auhyb1在铁血红素周围形成钳型结构，通过强氢键和π -π堆积稳定了形成的配合物。这种相互作用反映了焓的降低，而金离子的存在诱导熵效应也有利于与铁血红素的结合。相比之下，Auhyb2通过AQ的醇基配位与铁相互作用，以及h键和π -π相互作用，形成稳定的醇氧化物金属配合物。这些分子相互作用可能增强传统低成本氨基喹啉类药物的抗疟效果，有助于破坏疟疾寄生虫中的血色素结晶。图形抽象

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来源期刊

Transition Metal Chemistry 化学-无机化学与核化学

CiteScore

3.60

自引率

0.00%

发文量

审稿时长

1.3 months

期刊介绍： Transition Metal Chemistry is an international journal designed to deal with all aspects of the subject embodied in the title: the preparation of transition metal-based molecular compounds of all kinds (including complexes of the Group 12 elements), their structural, physical, kinetic, catalytic and biological properties, their use in chemical synthesis as well as their application in the widest context, their role in naturally occurring systems etc. Manuscripts submitted to the journal should be of broad appeal to the readership and for this reason, papers which are confined to more specialised studies such as the measurement of solution phase equilibria or thermal decomposition studies, or papers which include extensive material on f-block elements, or papers dealing with non-molecular materials, will not normally be considered for publication. Work describing new ligands or coordination geometries must provide sufficient evidence for the confident assignment of structural formulae; this will usually take the form of one or more X-ray crystal structures.