Jamloki Ashutosh, Karthikeyan C, Hari Narayana Moorthy N S, Trivedi P
Department of Pharmacy, SGSITS, Indore, India.
Bioorg Med Chem Lett. 2006 Jul 15;16(14):3847-54. doi: 10.1016/j.bmcl.2006.04.014. Epub 2006 May 8.
A quantitative structure-activity relationship (QSAR) study has been performed on 5-amino-2-mercapto-1,3,4-thiadiazole based inhibitors of matrix metalloproteinases (MMPs) and a bacterial collagenase known as Clostridium histolyticum collagenase (ChC) to understand the structural features influencing the affinity of these inhibitors towards the enzyme. The compounds in the selected series were characterized by topological and fragmental descriptors calculated using QuaSAR module of molecular operating environment (MOE). An indicator variable was also assigned to account for the presence of amide function in vicinity of sulfonamide group in the parent structure. Correlations between different inhibitory activities and calculated predictor variables were established through stepwise multiple regression employing the method of least squares. The results of the study indicates that MMP inhibitory activity of 5-amino-2-mercapto-1,3,4-thiadiazoles can be successfully explained in terms of topology of the molecule. The obtained correlations also suggest that increase in the number of fluorine atoms in the aromatic ring will augment inhibitory activity of these molecules against all the MMPs probably by virtue of hydrogen bond interaction with some complementary groups in the active site of the enzymes. One prime requirement for better inhibition of MMPs (except for MMP-1) and ChC identified from the present study is the presence of amide function in vicinity of sulfonamide group in the parent structure as suggested by the presence of indicator variable in almost all correlations. While MMP-1 and ChC inhibitory activity of the compounds studied is shown to be dependent on Kier's first order carbon valence molecular connectivity index indicating that increase in branching and presence of heteroatoms in the molecule will improve the MMP-1 and ChC inhibitory potency of 5-amino-2-mercapto-1,3,4-thiadiazoles, correlations derived for other enzymes (MMP-2, MMP-8, MMP-9) are quite similar. In addition to the number of fluorine atoms and presence of indicator variable, MMP-2, MMP-8 and MMP-9 inhibitory activity of 5-amino-2-mercapto-1,3,4-thiadiazoles is found to be dependent on Kier's alpha modified index of third order in such a way that infer, terminally branched functions will increase the affinity of these molecules to the MMPs.
已对基于5-氨基-2-巯基-1,3,4-噻二唑的基质金属蛋白酶（MMPs）抑制剂以及一种名为溶组织梭菌胶原酶（ChC）的细菌胶原酶进行了定量构效关系（QSAR）研究，以了解影响这些抑制剂对该酶亲和力的结构特征。所选系列中的化合物通过使用分子操作环境（MOE）的QuaSAR模块计算的拓扑和片段描述符进行表征。还分配了一个指示变量，以说明母体结构中磺酰胺基团附近酰胺功能的存在。通过采用最小二乘法的逐步多元回归，建立了不同抑制活性与计算出的预测变量之间的相关性。研究结果表明，5-氨基-2-巯基-1,3,4-噻二唑的MMP抑制活性可以根据分子拓扑结构成功解释。所得相关性还表明，芳香环中氟原子数量的增加可能会通过与酶活性位点中的一些互补基团形成氢键相互作用，增强这些分子对所有MMPs的抑制活性。从本研究中确定的对MMPs（MMP-1除外）和ChC更好抑制的一个主要要求是母体结构中磺酰胺基团附近存在酰胺功能，这几乎在所有相关性中指示变量的存在都表明了这一点。虽然所研究化合物的MMP-1和ChC抑制活性显示取决于基尔一阶碳价分子连接性指数，这表明分子中分支增加和杂原子的存在将提高5-氨基-2-巯基-1,3,4-噻二唑对MMP-1和ChC的抑制效力，但针对其他酶（MMP-2、MMP-8、MMP-9）得出的相关性非常相似。除了氟原子数量和指示变量的存在外，发现5-氨基-2-巯基-1,3,4-噻二唑的MMP-2、MMP-8和MMP-9抑制活性取决于基尔三阶α修正指数，由此推断，末端分支功能将增加这些分子对MMPs的亲和力。
