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Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2023-10-28 , DOI: 10.1021/acs.jpcb.3c05738 Aranthya Hevelly Lima Costa 1 , Katyanna Sales Bezerra 1, 2 , José Xavier de Lima Neto 1 , Jonas Ivan Nobre Oliveira 1 , Douglas Soares Galvão 2 , Umberto Laino Fulco 1
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2023-10-28 , DOI: 10.1021/acs.jpcb.3c05738 Aranthya Hevelly Lima Costa 1 , Katyanna Sales Bezerra 1, 2 , José Xavier de Lima Neto 1 , Jonas Ivan Nobre Oliveira 1 , Douglas Soares Galvão 2 , Umberto Laino Fulco 1
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Malaria is a parasitic disease that, in its most severe form, can even lead to death. Insect-resistant vectors, insufficiently effective vaccines, and drugs that cannot stop parasitic infestations are making the fight against the disease increasingly difficult. It is known that the enzyme dihydroorotate dehydrogenase (DHODH) is of paramount importance for the synthesis of pyrimidine from the Plasmodium precursor, that is, for its growth and reproduction. Therefore, its blockade can lead to disruption of the parasite’s life cycle in the vertebrate host. In this scenario, PfDHODH inhibitors have been considered candidates for a new therapy to stop the parasitic energy source. Given what is known, in this work, we applied molecular fractionation with conjugated caps (MFCC) in the framework of the quantum formalism of density functional theory (DFT) to evaluate the energies of the interactions between the enzyme and the different triazolopyrimidines (DSM483, DMS557, and DSM1), including a complex carrying the mutation C276F. From these results, it was possible to identify the main features of each system, focusing on the wild-type and mutant PfDHODH and examining the major amino acid residues that are part of the four complexes. Our analysis provides new information that can be used to develop new drugs that could prove to be more effective alternatives to present antimalarial drugs.
中文翻译：
破译潜在抑制剂与恶性疟原虫 DHODH 酶之间的相互作用：计算视角
疟疾是一种寄生虫病，最严重的情况下甚至可以导致死亡。抗虫媒介、效果不足的疫苗以及无法阻止寄生虫感染的药物使得对抗这种疾病变得越来越困难。众所周知，二氢乳清酸脱氢酶（DHODH）对于从疟原虫前体合成嘧啶，即其生长和繁殖至关重要。因此，它的阻断可能会导致寄生虫在脊椎动物宿主中的生命周期中断。在这种情况下，Pf DHODH 抑制剂已被认为是阻止寄生能源的新疗法的候选者。鉴于已知的情况，在这项工作中，我们在密度泛函理论 (DFT) 的量子形式主义框架中应用了共轭帽分子分级分离 (MFCC)，以评估酶与不同三唑并嘧啶 (DSM483， DMS557 和 DSM1)，包括携带突变 C276F 的复合物。根据这些结果，可以确定每个系统的主要特征，重点关注野生型和突变型Pf DHODH，并检查属于四种复合物的主要氨基酸残基。我们的分析提供了可用于开发新药的新信息，这些新药可能被证明是现有抗疟药的更有效替代品。
更新日期：2023-10-28
中文翻译：
破译潜在抑制剂与恶性疟原虫 DHODH 酶之间的相互作用：计算视角
疟疾是一种寄生虫病，最严重的情况下甚至可以导致死亡。抗虫媒介、效果不足的疫苗以及无法阻止寄生虫感染的药物使得对抗这种疾病变得越来越困难。众所周知，二氢乳清酸脱氢酶（DHODH）对于从疟原虫前体合成嘧啶，即其生长和繁殖至关重要。因此，它的阻断可能会导致寄生虫在脊椎动物宿主中的生命周期中断。在这种情况下，Pf DHODH 抑制剂已被认为是阻止寄生能源的新疗法的候选者。鉴于已知的情况，在这项工作中，我们在密度泛函理论 (DFT) 的量子形式主义框架中应用了共轭帽分子分级分离 (MFCC)，以评估酶与不同三唑并嘧啶 (DSM483， DMS557 和 DSM1)，包括携带突变 C276F 的复合物。根据这些结果，可以确定每个系统的主要特征，重点关注野生型和突变型Pf DHODH，并检查属于四种复合物的主要氨基酸残基。我们的分析提供了可用于开发新药的新信息，这些新药可能被证明是现有抗疟药的更有效替代品。
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