以熱力學積分分子動力學模擬方法計算細胞外信號調節激酶與其抑制劑的結合自由能

Abstract

Erk激酶是Ras/Raf/MEK/ERK 訊號傳遞路徑的下游蛋白質，此路徑在某些癌症當中失調。我們選擇此蛋白質激酶並且使用分子動力學模擬來設計此蛋白質激酶新的抑制劑。先前的計算當中發現熱力學積分分子動力學模擬方法於計算蛋白質激酶一組抑制劑得到的相對自由能與實驗結果相近。在目前的研究上我們對新的類似化合物進行TI-MD計算是為了要搜尋出更好的抑制劑。一個在苯環上帶有OH官能基的類似物被發現比82A有更好的親和性約1.1千卡/莫耳。除此之外，我們探討於TI-MD方法中一步變換與三步變換上的表現之比較。另外，也討論關於不同的λ數目在計算上對於相對自由能上的影響。這些結果應該會對於未來TI-MD模擬以及這種類的抑制劑之設計會有一些幫助。

Erk is the downstream protein in the Ras/Raf/MEK/ERK signal transduction pathway which is deregulated in many cancers. In the present study, we select this kinase to design new inhibitors for this kinase using MD simulation. Previous computations have shown that thermodynamic integration (TI) MD simulation method is able to give relative binding free energy for a pair of inhibitors for this kinase in good agreement with experimental results. In the present study, we carried out TI-MD computations for new analogous compounds in searching for better inhibitors. An analog with –OH functional group on the benzene ring was found to have better affinity than the 82A ligand by 1.1 kcal/mol. In addition, we investigate how single mutational step performs compared with the triple mutational steps in the TI-MD method. Furthermore, effect of number of lambda points in the computed relative binding free energy was investigated as well. These results should be useful for further TI-MD simulation and inhibitor design of this kind.