针对多个Plasmodium falciparum激酶的基于结构的虚拟查揭示了抗疟疾化合物
Priya Godara1, K Sony Reddy2, Welka Sahu2
1Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, Ajmer, Rajasthan, 305817, India.
Molecular diversity
|December 21, 2023
概括
多向化合物提供了一种有希望的策略来对抗疟疾耐药性. 这项研究确定了针对多个Plasmodium falciparum激酶的新型抑制剂,显示出新的抗疟疾疗法的潜力.
科学领域:
- 药物的发现和开发.
- 寄生虫学的寄生虫学
- 药品化学 药品化学 是一个
背景情况:
- 对前线抗疟疾药物的新兴耐药性导致显著的死亡率,2021年有6.19万例死亡.
- 药物耐药性源于药物标的突变,这往往会产生健康成本,使多个标的同时突变不太可能发生.
研究的目的:
- 通过使用高通量虚拟查来识别针对六种Plasmodium falciparum (Pf) 激酶的多目标抑制剂.
- 评估这些化合物的潜力,以克服现有的抗疟疾药物耐药性.
主要方法:
- 使用高通量虚拟查 (HTVS) 选针对六种已验证的Plasmodium falciparum激酶的抑制剂.
- 对前六个预测的复合体进行了分子动力学模拟,以评估相互作用稳定性.
- 使用等级聚类来分析已识别的化合物与现有抗疟疾药物的结构分歧.
- 进行了体外寄生虫生长抑制试验,以验证顶级热门的有效性.
主要成果:
- 该研究确定了21个针对选择的Plasmodium falciparum激酶的多目标命中.
- 分子动态模拟证实了前六个复合物的稳定相互作用,包括Myricetin-MAP2,Quercetin-CDPK4,Myricetin-TMK,Quercetin-PKG,Salidroside-PK5和Salidroside-PI4K.
- 层次聚类表明,已识别的化合物在结构上与当前的抗疟疾药物不同,这表明交叉抵抗的可能性较低.
- 实验室试验显示出显著的抗疟疾活性,奎尔丁和米瑞丁的IC50值分别为1.84微米和3.93微米.
结论:
- 多向抑制剂是对抗Plasmodium falciparum耐药性的一个可行的策略.
- 已识别的化合物,特别是奎尔丁和米瑞丁,显示出作为新型抗疟疾药物候选药物的前景.
- 这些化合物的结构新性表明,与现有疗法交叉耐药性的风险降低.
相关概念视频
Malaria
Malaria pathogenesis in humans reflects a delicate interplay between parasite biology and host response. Clinical illness reflects a host’s immune response to the parasite’s asexual replication cycle, which is often asymptomatic in individuals with partial immunity. From the parasite's perspective, transmission between mosquito and human with minimal host pathology is evolutionarily advantageous. Among the six Plasmodium species infecting humans, P. falciparum and P. vivax dominate in global...
Anthelminthic Agents
Anthelmintic drugs differ significantly from antiparasitic therapies targeting protozoa, primarily due to differences in parasite biology. Whereas most protozoal treatments act on proliferating cells, anthelmintics are typically directed against mature, nonproliferative helminths. The therapeutic approach considers the helminth's reliance on neuromuscular coordination, glucose metabolism, and microtubular integrity for survival, reproduction, and localization within the host. Most anthelmintics...
Antiprotozoal Agents
Leishmaniasis is a widespread parasitic disease caused by several Leishmania species. It affects millions of people each year and remains a major public health problem in endemic regions. First-line treatment relies on pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate. Even so, how these drugs work has not been fully clear, especially their interaction with parasite-specific biochemical pathways. One key target is trypanothione reductase (TR), an enzyme that...


