Cyclodextrins are widely used for the solubilisation of poorly-soluble drugs in the formulations. However, current cyclodextrin formulation development strongly depends on trial-and-error in the laboratory, which is time-consuming and high cost. The aim of this research was to compare three modeling approaches (Docking, molecular dynamics (MD) and quantum mechanics (QM)) for cyclodextrin/drug complexation. Ibuprofen was used as a model drug. Binding free energy from three simulation methods was calculated as an important parameter to compare with the experimental results. Docking results from AutoDock Vina program showed that the scoring of complexation capability between ibuprofen and cyclodextrins is alpha (α), gamma (γ), beta (β), HP-beta-cyclodextrins, which indicated similar ranking with the results from phase solubility diagram experiments. MD simulation indicated that ibuprofen could form the stable complexes of ibuprofen with β, γ, HP-β-cyclodextrins, but not for alpha-cyclodextrin. Binding free energies from the MD simulation for β, γ, HP-β-cyclodextrins were -3.67, -0.67 and -3.87 kcal/mol, individually. Binding free energies of complexes of ibuprofen and β, γ, HP-β-cyclodextrins from QM simulations were -17.22, -14.75 and -20.28 kcal/mol, respectively. Results from all three modeling approaches showed similar ranking between ibuprofen and four cyclodextrin molecules as the experimental data. However, MD simulation with entropy calculation had the closest value to experimental data for β and HP-beta-cyclodextrins. Thus, MD simulation with MM-PBSA method may be fit to in silico screen for cyclodextrin formulations.

環糊精作為增溶劑廣泛應用於難溶藥的處方中。如今，關於環糊精包合物的研 究主要是實驗室中的反復試驗法，這種方法通常需要相當長的時間成本以及高 昂的費用。本研究的目的在於 Docking 模擬法，分子動力學模擬法和量子力學 模擬法對於環糊精包合物的比較研究。本研究中布洛芬被選為模型藥。三種模 擬方法計算得出的吉布斯自由能作為最終的輸出結果並與實驗結果進行比較。 本研究中使用 AutoDock Vina 進行 Docking 模擬，結果顯示與布洛芬結合能力由 弱到強的排序為α,γ,β, 羥丙基-β-環糊精，這與通過相溶解度試驗得出的試驗結 果一致。分子動力學預測布洛芬能與γ,β, 羥丙基-β-環糊精形成較為穩定的包合 物，但與α環糊精形成的包合物結構不穩定。 分子動力學模擬所計算出γ,β,羥丙基-β-環糊精和布洛芬包合物的吉布斯自由能分別爲-3.67，-0.67 和-3.87 kcal/mol。量子力學模擬法計算出的吉布斯自由能分別爲-17.22，-14.75 和-20.28 kcal/mol。所有的模擬實驗結果均顯示布洛芬與α環糊精結合能最弱，與羥丙基-β-環糊精之間結合能最強，和實驗結果相一致。通過比較三種模擬方法與實驗 結果所計算出的吉布斯自由能，得出分子動力學模擬法結合泊松波爾茲曼法計 算自由能最適合計算機模擬環糊精包合物的機構與計算吉布斯自由能。 關鍵字：環糊精，計算機分子模擬，分子對接，分子動力學，量子力學