陳 新，劉慧群

皖西學(xué)院材料與化工學(xué)院，安徽六安，237012

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吡唑并[3,4-b]吡啶衍生物對(duì)A1腺苷受體拮抗活性的定量構(gòu)效關(guān)系

陳 新，劉慧群

皖西學(xué)院材料與化工學(xué)院，安徽六安，237012

定量構(gòu)效關(guān)系(QSAR)；啟發(fā)式方法；吡唑并[3,4-b]吡啶衍生物；pKi

尋找高效選擇性的A1腺苷受體拮抗劑已成為近年來(lái)的研究熱點(diǎn)之一[1-5]。為此，人們合成了許多含氮雜環(huán)化合物吡唑并[3,4-b]吡啶衍生物、吡唑并[3,4-b]嘧啶衍生物和吡唑并[3,4-b]吡啶酮衍生物。Paola Fossa等人[1-2]用偏最小二乘法(PLS)研究了吡唑并[3,4-b]吡啶衍生物與A1腺苷受體結(jié)合常數(shù)的構(gòu)效關(guān)系，得到了15參數(shù)模型，但是該模型對(duì)吡唑并[3,4-b]吡啶衍生物類似物結(jié)合常數(shù)的預(yù)測(cè)結(jié)果與實(shí)驗(yàn)值偏差很大。鑒于CODESSA軟件[6]在預(yù)測(cè)化合物理化性質(zhì)和生物學(xué)性質(zhì)方面取得很好的效果[7-14]，本文采用該軟件進(jìn)行理論計(jì)算，以期得到吡唑并[3,4-b]吡啶衍生物與A1腺苷受體結(jié)合常數(shù)的理想的預(yù)測(cè)模型。

1 計(jì)算方法

2 結(jié)果與討論

計(jì)算得到的六參數(shù)和七參數(shù)模型分別表示為EQ-6和EQ-7，方程中的變量含義如表2所示：

pKi=(-21.02±1.767)BO-Cmax-(4690.1

±537.1)PC-Nmax+(0.0217±0.0028)ESP-HDSA+(7.6906±1.5239)FNSA-2+(1.1754±0.2284)ESPmin-(35.060±9.1307)ESP-FHBCA-(289.59±36.904)

EQ-6

pKi=(-21.672±3.3076)BO-Cmax-(3789.7±466.30)PC-Nmax+(0.027597±0.0033222)ESP-HDSA+(7.0889±1.4223)FNSA-2-(57.812±6.9588)NRI-Nmin-(58.301±11.661)ESP-FHBCA+(1780.9±493.14)HACA-2-(221.74±28.374)

EQ-7

序號(hào)R序號(hào)R序號(hào)R序號(hào)R1NHCH2CH2CH39NH-c-C3H515NHCH2CH2CH323NH-c-C3H52NHCH2CH2Ph10NH(CH2)2OCH2CH316NH-c-C3H524NHCH2CH2CH33NH(CH2)2OCH2CH311NH-c-C6H1117NH(CH2)3CH325NHC4H94NHCH2Ph12pyrrolidin-1-18NH(CH2)2OCH2CH35NH-c-C3H513NHCH2Ph19NH-c-C6H116NH-c-C6H1114NHCH2CH2Ph20pyrrolidin-1-7pyrrolidin-1-214-Morpholino8NHPh22NHCH2CH2Ph

序號(hào)R1R序號(hào)R1R26CH3NH-c-C3H548CH(CH3)2NH-c-C3H527CH3NHCH2CH2CH349CH(CH3)2NHCH2CH2CH328CH3pyrrolidin-1-50CH(CH3)2pyrrolidin-1-29CH34-Morpholino51CH(CH3)24-Morpholino30CH3NHCH2Ph52CH(CH3)2NHCH2Ph31CH3NHCH2CH2Ph53CH(CH3)2NHCH2CH2Ph32CH3NHCH2CH2-p-C6H4-CH354CH(CH3)2NHCH2CH2-p-C6H4-CH333CH3NHCH2CH2-p-C6H4-OCH355CH(CH3)2NHCH2CH2-p-C6H4-OCH334C2H5NHCH2CH2-p-C6H4-CH356CH(CH3)2NHCH2CH2-o-C6H4-Cl35C2H5NHCH2CH2-p-C6H4-OCH357CH(CH3)2NHCH2CH2-m-C6H4-Cl36C2H5NHCH2CH2-o-C6H4-F58CH(CH3)2NHCH2CH2-p-C6H4-Cl37C2H5NHCH2CH2-m-C6H4-F59C4H9NH-c-C3H538C2H5NHCH2CH2-p-C6H4-F60C4H9NHCH2CH2CH339C2H5NHCH2CH2-o-C6H4-Cl61C4H9pyrrolidin-1-40C2H5NHCH2CH2-m-C6H4-Cl62C4H94-Morpholino41C2H5NHCH2CH2-p-C6H4-Cl63C4H9NHCH2Ph42C3H7NH-c-C3H564CH(CH3)C2H5NH-c-C3H543C3H7NHCH2CH2CH365CH(CH3)C2H5NHCH2CH2CH344C3H7pyrrolidin-1-66CH(CH3)C2H5NHCH2CH2Ph45C3H74-Morpholino67NHCH2CH2Ph46C3H7NHCH2Ph68NHCH2CH2-p-C6H4-CH347C3H7NHCH2CH2Ph

圖1 68種模型化合物的結(jié)構(gòu)圖

表1 六參數(shù)和七參數(shù)模型的結(jié)合強(qiáng)度預(yù)測(cè)值與實(shí)驗(yàn)值

續(xù)表

注：序號(hào)中標(biāo)注a的化合物為測(cè)試集化合物，Exp為實(shí)驗(yàn)值，EQ-6(diff)表示EQ-6的預(yù)測(cè)值及其誤差。

表2 QSAR模型中描述符的含義

從方程EQ-6和EQ-7可以看出，兩者都共同使用了BO-Cmax(碳原子的最大鍵級(jí))、PC-Nmax(氮原子的最大部分電荷)、ESP-HDSA(氫鍵供體氫原子表面靜電勢(shì))、FNSA-2(電荷加權(quán)部分負(fù)電荷表面積的分?jǐn)?shù))和ESP-FHBCA(面積加權(quán)氫鍵供體原子靜電勢(shì))。不同之處在于EQ-6使用了參數(shù)ESPmin(分子表面的最小靜電勢(shì))，而EQ-7使用了參數(shù)NRI-Nmin(氮原子的最小親核反應(yīng)指數(shù))和HACA-2(氫鍵受體原子的面積加權(quán)表面電荷)。從中可以看出，影響吡唑并[3,4-b]吡啶衍生物及其類似物與A1腺苷受體結(jié)合強(qiáng)度的主要因素可以分為碳原子的最大鍵級(jí)、氫鍵相互作用和靜電相互作用三種類型。吡唑并[3,4-b]吡啶衍生物及其類似物中氮原子作為氫鍵受體，其帶電狀況既影響氫鍵作用的強(qiáng)度，也影響靜電作用的強(qiáng)度。

從預(yù)測(cè)結(jié)果來(lái)看，EQ-6和EQ-7對(duì)惰性化合物(pKi指定為5.00)預(yù)測(cè)誤差最大的為化合物63，絕對(duì)誤差分別為1.54和1.39，相對(duì)誤差分別為30.8%和27.8%；對(duì)于活性化合物預(yù)測(cè)誤差最大的為化合物4，絕對(duì)誤差分別為0.99和0.89，相對(duì)誤差分別為15.2%和13.7%。除此之外，EQ-6和EQ-7對(duì)訓(xùn)練集和測(cè)試集化合物(不論是惰性化合物還是活性化合物)預(yù)測(cè)值的相對(duì)誤差均在0(化合物43)～11.9%(化合物41)范圍之內(nèi)，而且預(yù)測(cè)結(jié)果非常接近，進(jìn)一步增加預(yù)測(cè)模型的參數(shù)意義不大。因此，EQ-6可以較好地吡唑并[3,4-b]吡啶衍生物及其類似物與A1腺苷受體結(jié)合強(qiáng)度。

3 結(jié) 論

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(責(zé)任編輯：汪材印)

2016-05-16

安徽省自然科學(xué)基金“載銀多孔配位聚合物的設(shè)計(jì)合成及其抗菌與緩釋性能研究”(1308085ME57)；皖西學(xué)院大學(xué)生研究性學(xué)習(xí)項(xiàng)目“多孔納米Fe3O4@SiO2固定組氨酸配合物催化氧化環(huán)己烷的性能研究”(wxxyx2016013)。

陳新(1972-)，安徽六安人，博士，副教授，主要研究方向：有機(jī)化學(xué)和藥物化學(xué)。

10.3969/j.issn.1673-2006.2016.10.031

O06

A

1673-2006(2016)11-0118-04