Homology modeling of gelatinase catalytic domains and docking simulations of novel sulfonamide inhibitors
Homology modeling of gelatinase catalytic domains and docking simulations of novel sulfonamide inhibitors
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DOI：
10.1021/jm980514x
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发表时间：
1999-05-20
影响因子：
7.3
通讯作者：
Yodo, M
中科院分区：
文献类型：
--
作者：
Kiyama, R;Tamura, Y;Yodo, M
明胶酶（MMP-9和-2）的催化结构域的三维模型已经构建的基础上的X-射线晶体结构的MMP-3。通过对与两种高效“探针”抑制剂复合的每个明胶酶模型进行模拟退火，探索了形成S1'亚位点下半部分但在其他MMPs晶体结构中显示出构象多样性的环段的构象。代表性的催化结构域模型已被选择为每个明胶酶从一组生成的构象的基础上的环的探针抑制剂的形状互补性。选择MMP-9的单一模型用于解释我们的新型磺酰胺类抑制剂的结构-活性关系。复杂模型的分子动力学（MD）模拟揭示了我们抑制剂结合机制的重要特征：（i）配体羧酸根基团与催化锌离子配位并与Glu 219侧链氢键合，（ii）磺酰氧之一与主链NH形成氢键（Leu 181和Ala 182），（iii）磺酰基取代基与S1'亚位点进行广泛的疏水接触。磺酰胺C-N-S-C扭转所特有的笨拙构象在通过将取代基正确地引入S1'亚位点实现第三种结合特征中起着重要作用。磺酰基取代基的直线延伸导致的抑制活性的提高归因于取代基与S1'亚位点之间的疏水接触的增加。改变取代基的直线形状的结构修饰导致活性的劣化。另一方面，为MMP-2选择的两个候选模型在S1'亚位点的底部形状上不同：一个具有通道样亚位点，另一个具有类似于MMP-9模型的口袋样亚位点。通过化学合成具有延长的磺酰基取代基的抑制剂，其末端烷基通过MD模拟显示从S1'亚位点底部突出到溶剂中，实验探测底部形状。这些抑制剂的明胶酶测定表明，取代基的延长显著降低了对MMP-9的活性，同时保留了对MMP-2的活性，因此增加了MMP-8和MMP-9之间的选择性。结果证实，MMP-9具有地板的口袋状S1'亚位点，MMP-2具有通道状S1'亚位点。
Three-dimensional models for the catalytic domain of gelatinases (MMP-9 and -2) have been constructed based on the X-ray crystal structure of MMP-3. Conformations of the loop segment which forms the bottom half of the S1' subsite but shows conformational diversity among the crystal structures of other MMPs have been explored by simulated annealing of each gelatinase model complexed with two highly potent "probe" inhibitors. Representative catalytic domain models have been selected for each gelatinase from the set of generated conformations based on shape complementarity of the loop to the probe inhibitors. The single model selected for MMP-9 was utilized to explain the structure-activity relationship of our novel sulfonamide inhibitors. Molecular dynamics (MD) simulations of the complex models revealed important features of the binding mechanism of our inhibitors: (i) the ligand carboxylate group coordinating to the catalytic zinc ion and hydrogen bonding to the Glu219 side chain, (ii) one of the sulfonyl oxygens forming hydrogen bonds with the main chain NHs (Leu181 and Ala182), (iii) the sulfonyl substituent making extensive hydrophobic contact with the S1' subsite. The gauche conformation exclusively adopted by the sulfonamide C-N-S-C torsion plays an important role in achieving the third binding feature by properly directing the substituent into the S1' subsite. Improvement of the inhibitory activity according to straight elongation of the sulfonyl substituent was attributed to an increase of the hydrophobic contact between the substituent and the S1' subsite. Structural modifications which alter the straight shape of the substituent lead to deterioration of the activity. On the other hand, the two candidate models selected for MMP-2 differ in the bottom shape of the S1' subsite: one with a channel-like subsite and the other with a pocket-like subsite resembling that of the MMP-9 model. The bottom shape was experimentally probed by chemical synthesis of inhibitors having elongated sulfonyl substituents whose terminal alkyl groups were shown by MD simulations to protrude from the S1' subsite bottom into the solvent. Gelatinase assays of these inhibitors showed that elongation of the substituent significantly reduces activity against MMP-9 while retaining activity against MMP-2, consequently increasing the selectivity between MMP-8 and -9. The results confirm that MMP-9 has a pocket-like S1' subsite with a floorboard and MMP-2 has a channel-like S1' subsite.