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物理化学学报  2018, Vol. 34 Issue (3): 314-322    DOI: 10.3866/PKU.WHXB201709042
所属专题: 密度泛函理论中的化学概念特刊
论文     
基于概念密度泛函理论磷酸酯类反应性物质毒性预测
丁晓琴1,*(),丁俊杰1,李大禹1,潘里1,裴承新2
1 北京药物化学研究所,北京 102205
2 国民核生化灾害防护国家重点实验室,北京 102205
Toxicity Prediction of Organoph Osphorus Chemical Reactivity Compounds Based on Conceptual DFT
Xiaoqin DING1,*(),Junjie DING1,Dayu LI1,Li PAN1,Chengxin PEI2
1 Beijing Institute of Pharmaceutical Chemistry, Beijing 102205, P. R. China
2 State Key Laboratory of NBC Protection for Civilian, Beijing 102205, P. R. China
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摘要:

磷酸酯类反应性物质是乙酰胆碱酯酶不可逆抑制剂。本文应用概念密度泛函理论(CDFT),采用四组条件(B3LYP/6-311++G(2d, 3p)/gas,B3LYP/6-311++G(2d, 3p)/CPCM/water,MP2/6-311++G(2d, 3p)/gas,MP2/6-311++ G(2d, 3p)/CPCM/water),对20多个磷酸酯反应性物质进行反应性描述指数计算,包括分子的化学势μ,绝对硬度η、亲电性指数ω、分子的前线轨道能量等分子整体描述参数,以及原子福井函数、自然键轨道(NBO)电荷、Wiberg键级、NBO键级等分子局域描述参数。通过对反应性描述指数以及定量构性关系(QSPR)方程预测结果的比较分析,得出结论:大多数化合物亲电进攻的反应中心发生在磷原子上;磷酸酯类化合物侧链乙胺基叔氮的质子化,将显著增强反应中心磷原子的亲电进攻能力;B3LYP/6-311++G(2d, 3p)/gas为最合理的计算条件;应用反应性描述指数建立的QSPR模型明显优于常规的2D-QSPR模型,能够用于乙酰胆碱酯酶不可逆抑制剂的精确毒性预测。

关键词: 概念密度泛函理论反应性指数有机磷酸酯类乙酰胆碱酯酶不可逆抑制剂定量构性关系    
Abstract:

Following the exceptional success of density functional theory (DFT) in the realm of quantum chemistry, the conceptual DFT (CDFT) method has been widely used for describing the dynamic reactivity index of reactive chemicals in recent years. Reactive chemicals refer to those that bind covalently to biological macromolecules; in other words, the binding of the ligand with the receptor or enzyme involved with the breakage of the old bond and the process of formation of the new bond. Organophosphorus AChE irreversible inhibitors are reactive chemicals. In the present work, we calculated the reactivity descriptors for AChE irreversible inhibitors (organophosphate compounds), including some pesticides and chemical warfare agents, by the CDFT method at the B3LYP/6-311++G(2d, 3p)/gas, B3LYP/6-311++G(2d, 3p)/CPCM/water, MP2/6-311++G(2d, 3p)/gas, MP2/6-311++G(2d, 3p)/CPCM/water levels, in order to analyze their reactivity and determine the optimal parameters for calculation. Reactivity descriptors such as chemical potential (μ), vertical ionization energy (I), vertical electronic affinity (A), molecular absolute hardness (η), electrophilicity (ω), condensed atomic Fukui function, and varied natural bond orbital (NBO) bond order, were used to identify changes in the reactivity of these compounds in the gas and aqueous phases with the conductor-like polarizable continuum model (CPCM) model. The values of the reactivity descriptors and quantitative structure-property relationship (QSPR) models indicated that: the center of the phosphor atom (P) was the nucleophilic reaction site with AChE for most of selected compounds; substituted tertiaryamine protonization in organophosphorus compounds greatly enhanced the ele`s\vl VE`s\vl V the P reaction center; and as a whole, conformation did not have a significant effect on the reactivity for theDFT/B3LYP method, with an exception for the MP2 method which showed a comparative instability in results. The initial QSPR model in training sets of pLD50 with stepwise regression analysis shows that the B3LYP/6-311++G(2d, 3p)/gas level can provide a better result than the MP2 level and in the water phase, and provides a good representation of the molecular structure-toxicity relationship. These predictions for the compounds surpass those obtained by conventional QSPR equations, which do not consider electron transfer in the phosphorylated or aged process, thereby providing unreliable predictions. The proposed reactivity concept using the CDFT principle possesses a definite physical meaning, reflects the dynamic reactivity from the ground state of the molecular structure, and can be applied to toxicity predictions for AChE irreversible inhibitors with greater precision and stability.

Key words: CDFT    Reactivity descriptors    Organophosphate    AChE irreversible inhibitors    QSPR
收稿日期: 2017-08-04 出版日期: 2017-09-04
中图分类号:  O641  
通讯作者: 丁晓琴     E-mail: dingxiaoqin2008@126.com
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引用本文:

丁晓琴,丁俊杰,李大禹,潘里,裴承新. 基于概念密度泛函理论磷酸酯类反应性物质毒性预测[J]. 物理化学学报, 2018, 34(3): 314-322, 10.3866/PKU.WHXB201709042

Xiaoqin DING,Junjie DING,Dayu LI,Li PAN,Chengxin PEI. Toxicity Prediction of Organoph Osphorus Chemical Reactivity Compounds Based on Conceptual DFT. Acta Phys. -Chim. Sin., 2018, 34(3): 314-322, 10.3866/PKU.WHXB201709042.

链接本文:

http://www.whxb.pku.edu.cn/CN/10.3866/PKU.WHXB201709042        http://www.whxb.pku.edu.cn/CN/Y2018/V34/I3/314

Name pLD50(rat)/(μg·kg-1) HOMO/(a.u.) LUMO/(a.u.) (L-H)a/eV P-charge fP(r) b
sarin 3.66 -0.30853 -0.01552 7.97327 2.39323 0.04233
soman 4.01 -0.30182 -0.01629 7.76973 2.39693 0.03169
tabun 3.31 -0.27529 -0.02279 6.87093 2.30801 0.04865
amiton 3.22 -0.21574 -0.01174 5.55117 2.22079 -0.00280
amiton+NHc 3.22 -0.37238 -0.14426 6.20751 2.25657 0.03566
VX 4.43 -0.20997 -0.01374 5.33973 2.00131 -0.00064
VX+NH 4.43 -0.37102 -0.13840 6.32996 2.02916 0.04545
GV 3.72 -0.23216 -0.01579 5.88777 2.55768 0.01366
GV+NH 3.72 -0.37391 -0.16792 5.60532 2.56211 0.03655
GV+NH-Ninvertd 3.72 -0.37658 -0.16635 5.72069 2.55776 0.03711
methamidophos 1.82 -0.25407 -0.01860 6.40752 2.10542 0.04128
paraoxon 3.15 -0.27701 -0.10030 4.80856 2.59854 0.01961
parathion 2.70 -0.26027 -0.10055 4.34624 2.06917 0.01876
dichlorvos 1.82 -0.25291 -0.02184 6.28778 2.58576 0.02170
DMMPA -0.38 -0.24616 -0.01311 6.34166 2.53048 0.02865
leptophos 0.87 -0.25020 -0.06096 5.14952 1.83612 0.01947
diisopropyle 2.89 -0.30782 -0.01442 7.98388 2.61035 0.02460
EDMM 4.27 -0.22366 -0.01408 5.70301 1.99680 0.00515
EDMM+NH 4.27 -0.37686 -0.16074 5.88097 2.01884 0.04085
trichlorfon 0.80 -0.30221 -0.05833 6.63637 2.38787 0.03141
表1  训练集分子的pLD50毒性、前线轨道能量和能差、磷原子的NBO电荷和亲电反应指数fp-(r)
Name I/eV A/eV (I-A)/eV μ/eV η/eV ω/eV
sarin 10.62338 0.40002 10.22336 -5.51170 5.11168 2.97151
soman 10.12265 0.34783 9.77482 -5.23524 4.88741 2.80391
tabun 9.53891 0.32610 9.21280 -4.93250 4.60640 2.64084
amiton 7.72701 0.38711 7.33990 -4.05706 3.66995 2.24251
amiton+NHc 12.12186 -2.72825 14.85011 -4.69681 7.42506 1.48551
VX 7.47529 0.36253 7.11276 -3.91891 3.55638 2.15919
VX+NH 12.11138 -2.63416 14.74554 -4.73861 7.37277 1.52279
GV 8.28013 0.32166 7.95847 -4.30089 3.97924 2.32427
GV+NH 12.30365 -3.16866 15.47231 -4.56749 7.73616 1.34834
GV+NH-Ninvert 12.37832 -3.14093 15.51924 -4.61870 7.75962 1.37457
methamidophos 9.11244 0.43004 8.68240 -4.77124 4.34120 2.62194
paraoxon 9.32693 -0.82099 10.14792 -4.25297 5.07396 1.78241
parathion 8.77754 -0.86911 9.64666 -3.95422 4.82333 1.62085
dichlorvos 8.95219 0.36877 8.58343 -4.66048 4.29171 2.53047
DMMPA 8.57309 0.40989 8.16320 -4.49149 4.08160 2.47127
leptophos 8.23588 -0.33412 8.57000 -3.95088 4.28500 1.82141
diisopropyl 10.45402 0.38487 10.06914 -5.41944 5.03457 2.91687
EDMM 8.09136 0.36412 7.72724 -4.22774 3.86362 2.31309
EDMM+NH 12.32954 -3.06068 15.39022 -4.63443 7.69511 1.39556
trichlorfon 10.10123 0.06345 10.03778 -5.08234 5.01889 2.57330
表2  训练集分子整体反应性指数
Name bo1_X a bo2_O-C b bo3_N c bo4_N+1 d bo5_N-1 e bo6_P-X f bo7_O-C g
sarin 0.6085 0.8214 0.6085 0.6021 0.6579 0.0006 -0.0020
soman 0.6082 0.8166 0.6082 0.6037 0.6505 0.0189 -0.0294
tabun 0.7699 0.8402 0.7206 0.7302 0.6850 0.1290 0.0376
amiton 0.9321 0.7019 0.7019 0.7081 0.7338 0.0454 0.0170
amiton+NH 0.8793 0.8220 0.7432 0.7191 0.7860 0.0825 0.0360
VX 0.8870 0.8554 0.6996 0.7073 0.7289 0.0403 0.0089
VX+NH 0.8384 0.8345 0.7417 0.7213 0.7213 0.1171 0.0259
GV 0.7210 0.8567 0.6230 0.6173 0.6470 0.0404 0.0141
GV+NH 0.6735 0.9076 0.6486 0.6341 0.6968 0.1520 0.0300
GV+NH-Ninvert 0.6849 0.9041 0.6169 0.6144 0.6639 0.1609 0.0380
methamidophos 0.9137 0.8821 0.6958 0.6971 0.7437 0.0910 0.0233
paraoxon 0.6623 0.8439 0.6623 0.7123 0.5891 0.0732 0.0168
parathion 0.6471 0.8432 0.6471 0.7005 0.6544 0.0250 0.0181
dichlorvos 0.6652 0.8686 0.6652 0.6572 0.5746 0.0906 0.0257
DMMPA 0.7097 0.8797 0.7097 0.7171 0.6922 0.0897 0.0272
leptophos 0.6379 0.8736 0.6379 0.6178 0.6304 -0.0412 0.0144
diisopropyl 0.6351 0.8212 0.6351 0.6282 0.6744 0.0034 0.0128
EDMM 0.9166 0.8564 0.6878 0.6955 0.7202 0.0714 0.0197
EDMM+NH 0.8734 0.8300 0.7321 0.7115 0.7758 0.0976 0.0395
trichlorfon 0.7195 0.8686 0.7195 0.7036 0.7569 0.0212 0.0194
表3  关键原子间NBO键级及它们的得失1个电子后变化率
B3LYP/gas B3LYP/water MP2/gas MP2/water
HOMO/(a.u.) -0.30782 -0.31809 -0.46857 -0.47438
LUMO/(a.u.) -0.01442 -0.01244 0.03743 0.04190
LUMO-HOMO/eV 7.98388 8.31723 13.76907 14.04880
P1-charge 2.61035 2.62587 2.83067 2.84698
fP1-(r) 0.02460 0.02079 0.09101 0.07436
fC6-(r) -0.00767 -0.01016 0.06992 0.06209
fC8-(r) -0.01089 -0.0093 -0.00059 0.00064
P1―F3 bond order 0.6351 0.6268 0.5985 0.5908
P1―O4 bond order 0.7582 0.7711 0.7217 0.7333
P1―O5 bond order 0.7497 0.7710 0.7126 0.7316
O5―C6 bond order 0.8212 0.8018 0.7992 0.7779
O4―C8 bond order 0.8176 0.7999 0.7948 0.7761
表4  二异丙基氟磷酸酯优化结构及四组条件的计算结果比较
Compound pLD50(Exp.) Pred.1CDFT Residue1 Pred.2 2D-QSPR a Residue2
Training sets
sarin 3.66 3.67 0.01 3.64 -0.02
soman 4.01 3.94 -0.07 4.09 0.08
tabun 3.31 3.17 -0.14 3.25 -0.06
amiton+NH 3.22 3.65 0.43 3.18 -0.04
VX+NH 4.43 4.27 -0.16 4.53 0.10
GV+NH-Ninvert 3.72 3.73 0.01 3.69 -0.03
methamidophos 1.82 1.50 -0.32 1.99 0.17
paraoxon 3.15 3.03 -0.12 3.17 0.02
parathion 2.70 2.52 -0.18 2.62 -0.08
dichlorvos 1.82 1.96 0.14 1.91 0.09
DMMPA -0.38 -0.10 0.28 -0.15 0.23
leptophos 0.87 0.93 0.06 0.86 -0.01
diisopropyl 2.89 3.00 0.11 2.58 -0.31
EDMM+NH 4.27 4.15 -0.12 4.15 -0.12
trichlorfon 0.80 0.87 0.07 0.79 -0.01
Test sets
triazophos 0.97 0.83 -0.14 -0.08 -1.05
DCP 1.60 1.42 -0.18 1.63 0.03
TEP 0.10 1.33 1.23 2.74 2.64
DMMP -0.30 -0.28 0.02 1.59 2.01
24-optfreq25 - 6.39 1.15
27-optfreq25 - 5.69 0.67
表5  根据CDFT和传统2D-QSPR方法,方程组对训练集和测试集化合物pLD50预测结果
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