King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Life Sci. 2018 Aug 15;207:412-419. doi: 10.1016/j.lfs.2018.06.027. Epub 2018 Jun 25.
Lactoperoxidase (LPO) is an essential protein with broad spectrum antimicrobial activity present in mammalian milk. It imparts immunity to infants against wide range of pathogenic infections. Several in vitro studies have shown inhibition of LPO activity by pharmaceutical compounds including commonly used antibiotics such as ampicillin and gentamicin, and molecules like prednisolone, norepinephrine, etc. Prescription of such drugs to lactating mothers might have adverse health effects on infants. The aim of our study was the elucidation of the structural aspects of the inhibitory mechanism of ampicillin, gentamicin, amoxicillin, prednisolone and norepinephrine on LPO.
Three dimensional structure of camel LPO (cLPO) was developed using homology modeling and used for in silico experimental studies. The Schrödinger induced fit docking along with binding affinity estimation experiments were performed. The cLPO and Ligands were prepared using Protein Preparation Wizard and Ligprep modules available in Schrodinger suite. For estimating Binding affinity Prime Molecular Mechanics with Generalized Born and Surface Area (MMGB-SA) module was used.
The five drug ligands formed three to five hydrogen bonding interactions with cLPO. Amino acids Arg-231, Asp-232, Ser-370, Arg-371 and Glu-374 of cLPO were crucial for these interactions. The binding affinity values for gentamicin were highest and for norepinephrine were the lowest.
This study concludes that the five drug molecules show potential ability to inhibit the LPO activity. Further, a very high sequence similarity of cLPO with human LPO imparts high significance to these conclusions in relation to human health especially in new born infants.
乳过氧化物酶（LPO）是一种在哺乳动物乳汁中存在的具有广谱抗菌活性的必需蛋白。它赋予婴儿对多种致病性感染的免疫力。多项体外研究表明，包括常用抗生素氨苄西林和庆大霉素以及地塞米松、去甲肾上腺素等在内的药物化合物可抑制 LPO 活性。给哺乳期母亲开此类药物可能会对婴儿的健康产生不良影响。本研究旨在阐明氨苄西林、庆大霉素、阿莫西林、地塞米松和去甲肾上腺素对 LPO 抑制机制的结构方面。
使用同源建模方法构建骆驼 LPO（cLPO）的三维结构，并进行计算机实验研究。采用 Schrödinger 诱导契合对接和结合亲和力估算实验进行研究。使用 Schrodinger 套件中的 Protein Preparation Wizard 和 Ligprep 模块对 cLPO 和配体进行准备。使用 Prime 分子力学与广义 Born 和表面积（MMGB-SA）模块估算结合亲和力。
五种药物配体与 cLPO 形成三到五个氢键相互作用。cLPO 的氨基酸 Arg-231、Asp-232、Ser-370、Arg-371 和 Glu-374 对这些相互作用至关重要。庆大霉素的结合亲和力值最高，而去甲肾上腺素的结合亲和力值最低。
本研究得出结论，这五种药物分子具有抑制 LPO 活性的潜力。此外，cLPO 与人 LPO 的序列高度相似，这使得这些结论在涉及人类健康，特别是新生儿健康方面具有重要意义。
