Acta Phys. -Chim. Sin. ›› 2018, Vol. 34 ›› Issue (3): 314-322.doi: 10.3866/PKU.WHXB201709042

Special Issue: Special issue for Chemical Concepts from Density Functional Theory

Previous Articles    

Toxicity Prediction of Organoph Osphorus Chemical Reactivity Compounds Based on Conceptual DFT

Xiaoqin DING1,*(),Junjie DING1,Dayu LI1,Li PAN1,Chengxin PEI2   

  1. 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
  • Received:2017-08-04 Published:2017-12-18
  • Contact: Xiaoqin DING


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 electrophilic attackingability of 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