一個與癌症相關激酶-配合體的對位研究

Abstract

抑制PDK1的活性是抗癌藥物研發的目標之一。在本研究中，使用Autodock程式進行了ligand-PDK1複合體的docking計算，再現了目前已知的九個ligand-PDK1實驗結構。除了其中兩個ligand以外，其餘的錯合體結合能與實驗所得IC50值呈現相關性。為了設計更好的抑制劑，我們做了一些低IC50值的藥物UCN(nM)、BIM8(μM)，及其衍生物的docking計算。有幾個得到更大的結合能，代表其為更好的抑制劑，並討論穩定複合體之作用力。另外，也計算了一系列以Celebrex為基礎的化合物，其計算結果與實驗IC50的相關度也報告、討論於此論文中。

Inhibition of PDK1 kinase activity is one of the targets in developing cancer drug. In the present study, a docking calculation for ligand-PDK1 kinase complexes was carried out using the Autodock program. Experimental binding modes of 9 available lignad-PDK1 structures were reproduced. The binding energies of these complexes were correlated well with experimental IC50 values except 2 ligands. Toward designing better inhibitors, we have carried out docking calculation for a number of derivatives of the inhibitors of low IC50 value, UCN (in nM range) and BIM8. The calculations for several derivatives gave lower binding energy, suggesting that they are better inhibitors. The rationals of the calculated binding energies are discussed. In addition, calculations for a series of celebrex-based compounds were also carried out. Their correlations with experimental available IC50 values are discussed as well.