本文選題：結(jié)構(gòu)參數(shù) + 熱力學(xué)參數(shù)��； 參考：《山西醫(yī)科大學(xué)》2014年碩士論文

【摘要】：目的：使用促滲劑是提高藥物經(jīng)皮吸收的最有效和方便的方法，但其種類繁多，結(jié)構(gòu)各異，逐一篩選非常困難，建立定量構(gòu)效關(guān)系模型（QSAR）可對(duì)未知化合物的活性進(jìn)行預(yù)測(cè)，從而指導(dǎo)促滲劑的篩選和結(jié)構(gòu)優(yōu)化。本文將密度泛函和從頭算的量子化學(xué)計(jì)算方法用于41種萜類化合物結(jié)構(gòu)參數(shù)及熱力學(xué)參數(shù)的確定，以建立一種預(yù)測(cè)精度高的萜類化合物經(jīng)皮促滲活性QSAR模型。 方法：選擇41種萜類化合物作為模型促滲劑，以氟哌啶醇（HP）為模型藥物。采用量子化學(xué)法來確定化合物的結(jié)構(gòu)參數(shù)及熱力學(xué)參數(shù)。首先，利用內(nèi)坐標(biāo)做出萜類化合物的分子結(jié)構(gòu)，在GaussianView軟件中對(duì)以上各單體進(jìn)行構(gòu)造，其次，在HF/3-21G、B3LYP/6-311++G(2d,p)水平下進(jìn)行各個(gè)單體的結(jié)構(gòu)優(yōu)化，得到最優(yōu)結(jié)構(gòu)，，最后，從out文件中采集或計(jì)算藥物的結(jié)構(gòu)參數(shù)及熱力學(xué)參數(shù)：包括自然電荷（CN）、APT電荷（CAPT）、Mulliken電荷（CMu）、表面靜電勢(shì)（包含：最大值（VS,max）、最小值（VS,min）、總面積（VS,ta）、正面積（VS,pa）、負(fù)面積（VS,na））、雙重偶極距（D）、分子量（M）、分子體積（Vm）、最高占據(jù)分子軌道（EHOMO）、最低未占據(jù)分子軌道（ELUMO）、前線軌道能極差（EH-U）、硬度（η）、化學(xué)勢(shì)（λ）、焓（H）、吉布斯自由能（G）、熵（S）、摩爾熱容（Cp）。分別考察41種萜類促滲劑對(duì)氟哌啶醇藥物的促滲活性，用Kp來表示。本文的Kp值均來自L. Kang等人的文獻(xiàn)，L. Kang等首先建立氟哌啶醇的高效液相色譜體外分析方法（HPLC），然后選擇離體皮膚，用流式細(xì)胞擴(kuò)散池測(cè)定用以表示促滲劑促滲活性指標(biāo)的變量滲透系數(shù)（Kp）。采用多元線性回歸建立萜類化合物的結(jié)構(gòu)參數(shù)及熱力學(xué)參數(shù)之間的QSAR模型。將所選擇的萜類化合物分為三類：含-OH的化合物、含-C=O的化合物、烴類或烯萜類化合物，分別建立這三類化合物的QSAR模型，即Ya、Yb、Yc，最后建立41種萜類化合物總的QSAR模型Yd，根據(jù)得到的R值來評(píng)價(jià)數(shù)據(jù)間的擬合程度，采用留一法對(duì)模型進(jìn)行內(nèi)部檢驗(yàn)，通過計(jì)算RMSE值來進(jìn)行模型外部檢驗(yàn)。 結(jié)果：采用后退法回歸建立的模型分別Ya=-6.107+10.873CAPT+14.485CMu-0.002VS,max-0.013VS,min+0.091VS,ta-1.496D+0.099M-0.068Vm-64.572Cp（n=22）、Yb=-10.675-17.105CMu-2.701D+0.067M（n=12）、Yc=0.491-0.014M+40.222η（n=7）、Yd=-15.823-0.008VS,max-0.009VS,min+0.02VS,ta-0.319D-51.952λ-11.15Cp（n=41）。模型的R值分別為0.933、0.860、0.985、及0.809，S分別為0.849、0.796、0.176、及1.000，經(jīng)留一法交互驗(yàn)證得到RCV2=0.871、0.739、0.970、0.6540.5，對(duì)模型的準(zhǔn)確性能檢驗(yàn)得RMSE分別為0.627、0.650、0.133、0.910。根據(jù)RCV2和RMSE值可知模型a、b、c、d預(yù)測(cè)準(zhǔn)確程度較高；且模型的穩(wěn)定性和預(yù)測(cè)精度較好。 由模型a、b、c、d表明，促滲劑促滲效果主要與APT電荷、Mulliken電荷、表面靜電勢(shì)（最大值、最小值、總面積）、雙重偶極距、分子量、分子體積、硬度、化學(xué)勢(shì)、摩爾熱容等因素有關(guān)。在大多數(shù)情況下，最大靜電勢(shì)越小、最小靜電勢(shì)越小、靜電勢(shì)的總面積越大、雙重偶極矩越小、摩爾熱容越小的萜類化合物的促滲能力越強(qiáng)。 結(jié)論:本課題所建立的模型均具有統(tǒng)計(jì)學(xué)意義，與L. Kang文中所建立模型相比，本文所建立的QSAR模型的預(yù)測(cè)精度相對(duì)較高，穩(wěn)定性較好，從而進(jìn)一步更好的指導(dǎo)萜類化合物的活性預(yù)測(cè)和結(jié)構(gòu)優(yōu)化，提高了促滲劑篩選的預(yù)測(cè)準(zhǔn)確性。
[Abstract]:Objective: the use of the promoter is the most effective and convenient method to improve the drug transdermal absorption, but it has a wide variety and different structures. It is very difficult to screen one by one. A quantitative structure-activity relationship model (QSAR) can be used to predict the activity of the unknown compounds, so as to guide the screening and structural optimization of the enhancers. The quantum chemical calculation method is used to determine the structural parameters and thermodynamic parameters of 41 terpenoids, so as to establish a QSAR model for the percolation activity of terpenoids with high prediction accuracy.
Methods: 41 terpenoids were selected as model penetration enhancers and haloperidol (HP) was used as model drug. Quantum chemical method was used to determine the structural parameters and thermodynamic parameters of the compounds. First, the molecular structures of terpenoids were made using the internal coordinates, and the above monomers were constructed in the GaussianView software, followed by HF/3-21G, B At the level of 3LYP/6-311++G (2D, P), the structure of each monomer is optimized and the optimal structure is obtained. Finally, the structural parameters and thermodynamic parameters of the drug are collected or calculated from the out file, including the natural charge (CN), the APT charge (CAPT), the Mulliken charge (CMu), the surface electrostatic potential (including the maximum value (VS, max), the minimum value of the VS, the total area, and the total area. VS, PA, VS, Na), double polar distance (D), molecular weight (M), molecular volume (Vm), the highest occupying the molecular orbital (EHOMO), the lowest unoccupied molecular orbital (ELUMO), the front orbital energy difference (EH-U), the hardness (NA), the enthalpy (H), the Gibbs free energy (G), the entropy, and the molar heat capacity. The percolation activity of the acetamol drug is expressed in Kp. The Kp values of this article are all from the literature of L. Kang et al., L. Kang and so on first establish the high performance liquid chromatography (HPLC) method of haloperidol (HPLC), and then choose the isolated skin and determine the variable osmotic coefficient (Kp) using the flow cell diffusion pool to indicate the index of the promoter activity of the promoter (Kp). The QSAR model between the structural parameters and the thermodynamic parameters of terpenoids is established by the meta linear regression. The selected terpenoids are divided into three categories: -OH containing compounds, -C=O containing compounds, hydrocarbons or terpenoids, and the QSAR models of these compounds, namely, Ya, Yb, Yc, and the final establishment of the total QSAR of 41 terpenoids. Model Yd, according to the obtained R value to evaluate the degree of data fitting, using one method to carry out the internal test of the model, through the calculation of the RMSE value to carry out the model external test.
Results: the models established by regression method are Ya=-6.107+10.873CAPT+14.485CMu-0.002VS, max-0.013VS, min+0.091VS, ta-1.496D+0.099M-0.068Vm-64.572Cp (n=22), Yb=-10.675-17.105CMu-2.701D+0.067M (n=12), Yc=0.491-0.014M+40.222 (n=7), Yd= -15.823-0.008VS, max-0.009VS, ta-1.496D+0.099M-0.068Vm-64.572Cp. The R values of the model are 0.933,0.860,0.985, and 0.809, S are 0.849,0.796,0.176, and 1 respectively, and RCV2=0.871,0.739,0.970,0.6540.5 is obtained by one method. The accuracy of the model is verified to be 0.627,0.650,0.133,0.910. based on RCV2 and RMSE values for a, B, C, and the model is more accurate. The stability and prediction accuracy are good.
The model a, B, C, and d show that the penetration enhancers are mainly related to APT charge, Mulliken charge, surface static potential (maximum, minimum, total area), double even distance, molecular weight, molecular volume, hardness, chemical potential, mole heat capacity and so on. In most cases, the smaller the maximum electrostatic potential is, the smaller the minimum electrostatic potential is, the more the total area of the electrostatic potential is, the more the total area is. The smaller the double dipole moment and the smaller the molar heat capacity, the stronger the penetration of terpenes.
Conclusion: the model established in this project is of statistical significance. Compared with the model established in L. Kang, the prediction accuracy of the QSAR model is relatively high and the stability is better, thus further better guiding the activity prediction and structural optimization of terpenoids, and improving the accuracy of the prediction of the selection of the permeating agent.
【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R943

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