Kumar R Barani, Suresh M Xavier
Department of Bioinformatics, Sathyabama University, Chennai, India.
Pharmacogn Mag. 2013 Apr;9(34):89-95. doi: 10.4103/0973-1296.111239.
Tamulotoxin (TmTx) from Buthus tamulus was found to be a highly venomous toxin which accelerates the neurotransmitter release that directly affects the cardiovascular tissues and the respiratory system leading to death. TmTx from red Indian scorpion is a crucial inhibitor for Ca(2+) activated K(+) channel in humans.
The study is aimed at the identification of potential inhibitors of TmTx through pharmacophore based inhibitor screening and understanding the molecular level interactions.
The potential inhibitors for TmTx were identified using pharmacophore model based descriptor information present in existing drugs with the analysis of pharmacokinetic properties. The compounds with good ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) descriptors were subjected to molecular interaction studies. The stability of bound toxin-inhibitor complex was studied using molecular dynamics simulation over a period of one nanosecond.
From a dataset of 3406 compounds, few compounds were selected as potential inhibitors based on the generated best pharmacophore models, pharmacokinetic analysis, molecular docking and molecular dynamics studies.
In conclusion, two compounds containing better inhibition properties against TmTx are suggested to be better lead molecules for drug development in future and this study will help us to explore more inhibitors from natural origin against tamulotoxin.
发现来自印度红蝎子（Buthus tamulus）的塔穆洛毒素（TmTx）是一种剧毒毒素，它会加速神经递质释放，直接影响心血管组织和呼吸系统，导致死亡。来自印度红蝎子的TmTx是人类Ca(2+)激活K(+)通道的关键抑制剂。
本研究旨在通过基于药效团的抑制剂筛选来鉴定TmTx的潜在抑制剂，并了解分子水平的相互作用。
利用现有药物中基于药效团模型的描述符信息，并结合药代动力学性质分析，鉴定TmTx的潜在抑制剂。对具有良好ADMET（吸收、分布、代谢、排泄和毒性）描述符的化合物进行分子相互作用研究。使用分子动力学模拟在1纳秒的时间内研究结合的毒素-抑制剂复合物的稳定性。
从3406种化合物的数据集中，根据生成的最佳药效团模型、药代动力学分析、分子对接和分子动力学研究，筛选出了几种化合物作为潜在抑制剂。
总之，两种对TmTx具有较好抑制特性的化合物被认为是未来药物开发的更好先导分子，本研究将有助于我们从天然来源探索更多针对塔穆洛毒素的抑制剂。
