Kumari Diksha, Kaur Harjot, Palmo Tashi, Nargotra Amit, Singh Kuljit
Infectious Diseases Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
Nat Prod Res. 2024 Aug 19:1-7. doi: 10.1080/14786419.2024.2392749.
Natural product offers an ocean of biologically active compounds that have diverse functionality. Thus, the present study aims for the exploration of natural product molecules for their leishmanicidal potency. Primary evaluation at 50 µM concentration revealed that out of 560 molecules, 38 compounds demonstrated a percentage killing of >50%. Next, the dose-dependent investigation showed that six active hits displayed the IC value ranging from 0.47 to 14.2 µM. Further, the molecular docking analysis using the alpha fold structure of Sterol C-24 methyltransferase of (LdSMT) (an enzyme absent in mammalian host) unveiled the strong binding affinity with top two hits namely shatavarin IV (-7.9 kcal/mol) and 6-methoxydihydrochelerythrine (-7.6 kcal/mol). Also, studies were supported by the alterations in ergosterol content in the parasites treated with these two potent hits. In conclusion, our study suggests that the two potent hits inhibit the parasite growth by hindering sterol biosynthesis.
天然产物提供了大量具有多样功能的生物活性化合物。因此，本研究旨在探索具有抗利什曼原虫效力的天然产物分子。在50μM浓度下的初步评估显示，在560个分子中，有38种化合物的杀伤率超过50%。接下来，剂量依赖性研究表明，六个活性命中物的IC值范围为0.47至14.2μM。此外，使用（利什曼原虫的）甾醇C-24甲基转移酶（LdSMT）的α折叠结构进行的分子对接分析（一种在哺乳动物宿主中不存在的酶）揭示了与前两个命中物即 Shatavarin IV（-7.9 kcal/mol）和6-甲氧基二氢白屈菜红碱（-7.6 kcal/mol）的强结合亲和力。此外，用这两种有效命中物处理的寄生虫中麦角固醇含量的变化支持了这些研究。总之，我们的研究表明，这两种有效命中物通过阻碍甾醇生物合成来抑制利什曼原虫的生长。
