已知秋水仙鹼(colchicines)會與微管蛋白(tubulin)結合而干擾微管蛋白聚合之動力學，同時已有實驗證實此效應具有對抗癌症的效果。我們有興趣在於設計此類作用於秋水仙鹼結合位置(colchicine binding site)更好的藥物分子，在本篇研究中，我們利用全原子(all-atom)的分子動力學模擬方法，針對一些作用在微管蛋白其秋水仙鹼結合位置上的藥物分子研究，同時以MM-PBSA / MM-GBSA方法計算結合能。總共計算秋水仙鹼分子及其13個類似分子，部分分子之能量與已知實驗的抑制活性數值IC50值具有好的相關性。根據首先計算十個化合物的計算結果，我們更進一步設計三個新的藥物分子，此三個新設計分子皆較其他分子有更穩定之結合能。我們分析及討論幾個影響結合能計算之因素，包括: 修改化合物官能基的影響、蛋白質結合位置附近的胺基酸個別對總結合能的貢獻，以及分子間作用力的分析與討論，得到幾個修改官能基的建議包括: (1)官能基R4的位置置換為OH基，此OH基會與胺基酸α179THR產生穩定氫鍵，穩定化合物與微管蛋白的結合。(2)官能基R5的位置修改成具有苯環的酮類官能基，其官能基置換可與胺基酸β352LYS產生氫鍵，同時增加與胺基酸β248LEU之間的凡得瓦作用能，以及促進與β251ASP/β252ASP形成氫鍵。這些結果以及其他分析將有助於未來設計更好的藥物分子。

Ligands which bind at the colchicine site of tubulin, interfering with tubuline polymerization dynamics, have been showed to have anti-cancer effects. We are interested in drug design of a series of ligands binding at the colchicines binding site of tubulin. We used all-atom molecular dynamics simulation method to examine a number of ligands, binding with tubulin, using MM-PBSA/MM-GBSA approach. The calculated binding energies are reported. The calculated binding energies are in good accord with the available IC50 values of some ligands. Based on the results of the first-examined 10 ligands, we further designed 3 new ligands. Computations for these 3 ligands showed that the binding of these 3 ligands with tubulin are more stable than other ligands. Functional group substitution effects of this series of ligands, contributions of residues at the binding site of protein, correlation with available experimental results, and other factors are analyzed and discussed. These discussions lead to several suggestions of functional group substitutions, including (1) substitution of OH group at R4 site, which can form a hydrogen bond with the amino acid α179THR. (2) substitution of a carbonyl group with benzene ring (see text) at R5 site, which can form a hydrogen bond with the residue β352LYS, increase the vdw interaction with the residue β248LEU, and enhance formation of hydrogen bond with the residues β251ASP/β252ASP. These results and analysis should be of aid in designing better ligands.

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