蛋白激酶-A與數個小分子抑制劑複合體之分子動力學模擬:結合能計算
Abstract
蛋白激酶 ( protein kinase ) 是生物體訊息傳導途徑的重要成員之一，藉由磷酸化特定蛋白質，調控細胞酵素及傳遞訊息。
本研究中，我們的目的是利用分子動力學模擬方法，幫助設計PKA的抑製劑。首先我們從蛋白質資料庫(PDB)中選擇4個具有IC50值的PKA配體複合物，當中有其它類似的配體分子，再利用MM/PBSA計算小分子和PKA之間的結合自由能。
四個結晶結構當中，除了2C1A模擬結果，與原有的IC50值相比不具正相關，其它三個結構與現有IC50值比，則得到良好的相關性。經過模擬計算，我們進行討論和分析，取代配體當中的那些官能基能提高整體的親合力。基於這些結果，我們進一步設計五個新配位分子。最後，得到了幾點改變官能基的建議：（1）添加甲基在鹵化苯基的環上，可以增加與疏水性空腔間的凡得瓦作用力。（2）添加羥基於小分子骨架，此羥基上的氧原子容易與ASN 168/ ASP 184產生強而穩定的氫鍵作用力。
Protein kinase A plays significant role in a number of signaling pathways in cell, and is thought to be a potential drug target for treatments of several diseases by inhibiting its kinase activity. In the present study, we aimed to use molecular dynamics simulation method to aid in design of PKA inhibitors. We selected 4 ligand-PKA complexes, in which their ligands are analogous, from Protein data bank with available IC50 values, MM/PB(GB)SA was employed to investigate the binding between ligand and PKA. The calculated binding energies are in good accord with the available IC50 values of examined complexes except one. The calculated results were analyzed and discussed to aid in understanding which functional group substitutions can enhance the binding affinity. Based on these results,we further designed 5 new ligands to predict their binding affinities. The calculated results suggest the fillowing points to change the functional groups: (1) Adding a methyl group at the R1 or R3 position (see Figure in the text) of the single ring in the ligand can enhance the binding affinity. The van der Waals interaction is the main contributor in the total binding energy . (2) Adding a hydroxyl group at R5 position of the singl ring gave stable hydrogen bonds with the LYS 168 and ASP 184, increasing the binding affinity. These results together with the analysis above should be able to aid in design of PKA inhibitors analogous to the ligands investigated in the present study.
Protein kinase A plays significant role in a number of signaling pathways in cell, and is thought to be a potential drug target for treatments of several diseases by inhibiting its kinase activity. In the present study, we aimed to use molecular dynamics simulation method to aid in design of PKA inhibitors. We selected 4 ligand-PKA complexes, in which their ligands are analogous, from Protein data bank with available IC50 values, MM/PB(GB)SA was employed to investigate the binding between ligand and PKA. The calculated binding energies are in good accord with the available IC50 values of examined complexes except one. The calculated results were analyzed and discussed to aid in understanding which functional group substitutions can enhance the binding affinity. Based on these results,we further designed 5 new ligands to predict their binding affinities. The calculated results suggest the fillowing points to change the functional groups: (1) Adding a methyl group at the R1 or R3 position (see Figure in the text) of the single ring in the ligand can enhance the binding affinity. The van der Waals interaction is the main contributor in the total binding energy . (2) Adding a hydroxyl group at R5 position of the singl ring gave stable hydrogen bonds with the LYS 168 and ASP 184, increasing the binding affinity. These results together with the analysis above should be able to aid in design of PKA inhibitors analogous to the ligands investigated in the present study.
Description
Keywords
蛋白激酶-A, 小分子抑制劑, 分子動力學模擬, 結合能計算