Computational Study of the Interactions between Antimalarial Chemotherapies with Folate Pathway Receptors and Telomerase Reverse Transcriptase

IF 2.4 Q3 Computer Science
Djogang Lucie Karelle, Forlemu Neville, Emadak Alphonse, Njabon Njankwa Eric, I. Patouossa, Nenwa Justin
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引用次数: 0

Abstract

Malaria is a life-threatening disease responsible for half a million death annually, and with nearly half of the world’s population at risk. The rapid drop in observed cases of malaria in the last two decades has been due to a combination of preventive and therapeutic remedies. However, the absence of a vaccine, new antimalarial chemotherapies and increased parasitic resistance have led to a plateau of infections and renewed research interest in target human and Plasmodium (the malaria parasite) receptors and new drugs. In this study, the impact of mutation on the affinity on antimalarial drugs with the bifunctional enzyme complex, dihydrofolate reductase (DHFR) is explored. In addition, homology modeling is used to build the three-dimensional models of the enzymes Plasmodium telomerase reverse-transcriptase (pf-TERT) and Plasmodium dihydropteroate synthetase (pf-DHPS) to determine their affinity with antimalarial drugs. The interaction energies and stable complexes formed between these enzymes and antimalarial drugs (chloroquine, artemisinin, primaquine, pyrimethamine, sulfadoxine and pentamidine) were modelled using AutoDock vina. Our data indicate that pf-TERT and pf-DHPS form stable complexes with the antimalarial ligands with affinity ranging from 𕒸.0 to 𕒺.9 kcal/mol. The affinity with crystal structures of DHFR receptors was higher ranging from 𕒺.0 to 󔼒.0 kcal/mol. The affinity to DHFR also decreases with the mutation a confirmation of the source of resistance. The highest affinity interaction for all the receptors modeled is observed with Artemisinin a benchmark antimalarial drug. This can be attributed to the size, shape and dipolar surface of the ligand. The observed complexes are stabilized by strategic active site polar and non-polar contacts.
抗疟化疗与叶酸通路受体和端粒酶逆转录酶相互作用的计算研究
疟疾是一种威胁生命的疾病,每年造成50万人死亡,世界上近一半的人口处于危险之中。在过去二十年中观察到的疟疾病例的迅速下降是由于预防性和治疗性补救措施的结合。然而,由于缺乏疫苗、新的抗疟化学疗法和寄生虫耐药性的增加,导致感染停滞不前,并重新燃起了对目标人类和疟原虫(疟原虫)受体和新药的研究兴趣。本研究探讨了突变对双功能酶复合物——二氢叶酸还原酶(DHFR)对抗疟药物亲和力的影响。此外,通过同源性建模建立了端粒酶逆转录酶(f- tert)和二氢蝶酸疟原虫合成酶(f- dhps)的三维模型,确定其与抗疟药物的亲和力。这些酶与抗疟药物(氯喹、青蒿素、伯氨喹、乙胺嘧啶、磺胺多辛和喷他脒)的相互作用能和形成的稳定配合物采用AutoDock vina建模。我们的数据表明,pf-TERT和pf-DHPS与抗疟疾配体形成稳定的配合物,其亲和力范围从𕒸。0到𕒺。9千卡每摩尔。DHFR受体的晶体结构亲和性较高,范围从𕒺。0到󔼒。0千卡每摩尔。对DHFR的亲和力也随着突变而降低,证实了耐药性的来源。观察到所有受体与基准抗疟药物青蒿素的亲和力相互作用最高。这可以归因于配体的大小、形状和偶极表面。所观察到的配合物通过策略活性位点极性和非极性接触来稳定。
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来源期刊
CiteScore
1.70
自引率
0.00%
发文量
0
审稿时长
3 months
期刊介绍: The Journal of Theoretical and Computational Chemistry (JTCC) is an international interdisciplinary journal aimed at providing comprehensive coverage on the latest developments and applications of research in the ever-expanding field of theoretical and computational chemistry. JTCC publishes regular articles and reviews on new methodology, software, web server and database developments. The applications of existing theoretical and computational methods which produce significant new insights into important problems are also welcomed. Papers reporting joint computational and experimental investigations are encouraged. The journal will not consider manuscripts reporting straightforward calculations of the properties of molecules with existing software packages without addressing a significant scientific problem. Areas covered by the journal include molecular dynamics, computer-aided molecular design, modeling effects of mutation on stability and dynamics of macromolecules, quantum mechanics, statistical mechanics and other related topics.
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