Abstract：
Xerantholide is a sesquiterpene lactone that has anti-gonorrhea and anti-plasmodium activities. We present gas-phase electronic structure calculations of the equilibrium geometry of xerantholide, its adiabatic electron affinity (AEA), adiabatic ionization energy (AIE) and the energy barrier (ΔE‡) connecting the lowest energy conformers of the sesquiterpene. The computations were performed with the B3LYP, M06-2X and ωB97xd variants of the density functional theory (DFT) in conjunction with large basis sets. With the inclusion of the vibrational zero point energy, the computed AEA range from 0.740 eV [B3LYP/Aug-CC-pVTZ] to 0.774 eV [B3LYP/6-311++G(d,p)], and the AIE is roughly 8.6 eV at all theoretical levels. At the B3LYP/Aug-CC-pVTZ level, the barrier (ΔE‡) connecting the two lowest energy conformers is predicted to be 13.9 kcal/mol. Based on the molecular docking analysis, xerantholide interacts with the active site of Neisseria gonorrhoeae carbonic anhydrase (NgCA) via hydrogen bonding, metal-acceptor interaction, and non-polar alkyl and pi-alkyl interactions. The predicted binding affinity of - 6.8 kcal/mol compares well with those obtained for standard NgCA inhibitors such as acetazolamide (-5.7 kcal/mol). A biomimetic model study involving xerantholide and zinc-tris imidazole ([ZnIm3]2+) ion was also carried out at different theoretical levels to estimate the interaction energy for the formation of the complex formed between the ligand and the active site model of NgCA. The binding free energy (ΔG) has been calculated to be - 28.5 kcal/mol at the B3LYP/6-311++G(d,p) level. The interaction mode observed in both the docking and the model calculations involves the lactone ring.
摘要：
Xerantholide是一种倍半萜内酯，具有抗淋病和抗疟原虫活性。我们介绍了色黄内酯平衡几何的气相电子结构计算，其绝热电子亲和力(AEA)，绝热电离能（AIE）和连接倍半萜的最低能量构象异构体的能垒（ΔE®）。计算是用B3LYP进行的，密度泛函理论（DFT）的M06-2X和ωB97xd变体与大基集相结合。包含振动零点能量，计算的AEA范围从0.740eV[B3LYP/Aug-CC-pVTZ]到0.774eV[B3LYP/6-311++G（d，p)],在所有理论水平上，AIE约为8.6eV。在B3LYP/Aug-CC-pVTZ级别,连接两个最低能量构象异构体的势垒(ΔE®)预计为13.9kcal/mol。基于分子对接分析,黄药内酯通过氢键与淋病奈瑟菌碳酸酐酶（NgCA）的活性位点相互作用，金属-受体相互作用，和非极性烷基和π-烷基相互作用。预测的〜6.8kcal/mol的结合亲和力与标准NgCA抑制剂如乙酰唑胺(〜5.7kcal/mol)获得的亲和力比较好。还在不同的理论水平上进行了涉及黄花素和锌-三咪唑（[ZnIm3]2）离子的仿生模型研究，以估计配体与NgCA活性位点模型之间形成的复合物的相互作用能。在B3LYP/6-311++G（d，P）水平。在对接和模型计算中观察到的相互作用模式涉及内酯环。
