【摘要】：酪氨酸酶是黑色素生成的關(guān)鍵限速酶,黑色素的含量與分布決定著人體皮膚和毛發(fā)的顏色。在人體中,酪氨酸酶活性增強(qiáng),使黑色素生成增加,黑色素的過(guò)量生成會(huì)引起黃褐斑、色斑、老年斑等皮膚病。因此,抑制酪氨酸酶的活性可以有效減少黑色素的生成,從而起到淡化此類(lèi)斑痕的效果,進(jìn)而達(dá)到美白的作用。目前,已發(fā)現(xiàn)一些具有抑制酪氨酸酶活性的藥物,然而在實(shí)際應(yīng)用中往往存在一定的毒副作用,如光敏效應(yīng)、低穩(wěn)定性等,甚至有些具有致癌的危險(xiǎn)。因此,尋找具有低毒、高效的酪氨酸酶抑制劑成為當(dāng)前美容行業(yè)的當(dāng)務(wù)之急。大黃是我國(guó)的一種傳統(tǒng)中藥,具有“瀉熱通腸、逐瘀通經(jīng)、涼血解毒”的功效。研究表明,大黃水提取液對(duì)酪氨酸酶活性具有良好的抑制作用,然而對(duì)其具體作用的物質(zhì)基礎(chǔ)尚不明確,蒽醌類(lèi)成分是大黃的主要有效成分。因此,本研究以大黃中五種蒽醌類(lèi)成分(大黃素、大黃素甲醚、蘆薈大黃素、大黃酚、大黃酸)為研究對(duì)象,采用酶促動(dòng)力學(xué)反應(yīng)、光譜學(xué)及分子模擬等方法探討五種蒽醌類(lèi)成分對(duì)酪氨酸酶的抑制活性及其抑制機(jī)理。研究結(jié)果表明,五種蒽醌類(lèi)化合物均有抑制酪氨酸酶活性的作用,其作用大小為:大黃素甲醚大黃素蘆薈大黃素大黃酚大黃酸,其抑制類(lèi)型均為競(jìng)爭(zhēng)性抑制。光譜學(xué)和分子模擬研究表明,五種蒽醌類(lèi)化合物直接進(jìn)入酪氨酸酶的活性中心,主要通過(guò)疏水性作用力和靜電引力與酪氨酸酶活性中心的氨基酸殘基發(fā)生相互作用,從而引起了酪氨酸酶二級(jí)結(jié)構(gòu)的變化,導(dǎo)致酪氨酸酶內(nèi)源熒光的靜態(tài)猝滅。由于蒽醌類(lèi)成分進(jìn)入酪氨酸酶的活性位點(diǎn),阻礙了底物左旋多巴(L-DOPA)進(jìn)入該活性位點(diǎn),形成競(jìng)爭(zhēng)性抑制,這可能是最主要的抑制機(jī)理。此外,查閱相關(guān)文獻(xiàn),通過(guò)分子模擬軟件,建立了酪氨酸酶抑制劑的二維定量構(gòu)效關(guān)系(2D-QSAR),獲得預(yù)測(cè)能力較好的定量構(gòu)效關(guān)系(QSAR)模型,為進(jìn)一步優(yōu)化設(shè)計(jì)出新穎、高效的酪氨酸酶抑制劑提供了理論指導(dǎo)。
[Abstract]:Tyrosinase is a key rate-limiting enzyme for melanin production. The content and distribution of melanin determine the color of human skin and hair. In human body, tyrosinase activity is enhanced, melanin production is increased, excessive melanin production will cause melasma, macula, senile spot and other skin diseases. Therefore, inhibiting tyrosinase activity can effectively reduce the formation of melanin, thus play the role of desalination of such marks, and then achieve whitening effect. At present, some drugs have been found to inhibit tyrosinase activity, but in practical applications, there are often some toxic side effects, such as Guang Min effect, low stability, and even some carcinogenic risks. Therefore, the search for low-toxicity, high-efficiency tyrosinase inhibitors has become the top priority in the beauty industry. Rhubarb is a kind of traditional Chinese medicine in our country, which has the effect of "purging heat through intestine, removing blood stasis and clearing meridian, cooling blood and detoxifying". The results showed that the water extract of rhubarb had a good inhibitory effect on tyrosinase activity, but the material basis of its specific action was not clear. Anthraquinones were the main active components of rhubarb. Therefore, five anthraquinones in rhubarb (emodin, emodin methyl ether, aloe emodin, chrysophanol, Rhein) were used in this study. The inhibitory activity and mechanism of five anthraquinones on tyrosinase were studied by means of spectroscopy and molecular simulation. The results showed that all of the five anthraquinones had inhibitory effect on tyrosinase activity. The effects of emodin, aloe, emodin, chrysophanol and Rhein were all competitive inhibition. Spectroscopic and molecular simulation studies show that five anthraquinones directly enter the active sites of tyrosinase, and interact with the amino acid residues of tyrosinase by hydrophobic force and electrostatic force. Therefore, the secondary structure of tyrosinase was changed and the endogenous fluorescence of tyrosinase was quenched. The entry of anthraquinones into the active site of tyrosinase hinders the entry of substrates levodopa (L-DOPA) into the active site and forms a competitive inhibition which may be the main inhibitory mechanism. In addition, the two-dimensional quantitative structure-activity relationship (2D-QSAR) of tyrosinase inhibitors was established by consulting relevant literature and molecular simulation software. The quantitative structure-activity relationship (QSAR) model with good predictive ability was obtained, which was novel for further optimization. Efficient tyrosinase inhibitors provide theoretical guidance.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R284;R285

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本文編號(hào)：2256145