Kontogiorgis C A, Papaioannou P, Hadjipavlou-Litina D J
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 54124, Greece.
Curr Med Chem. 2005;12(3):339-55. doi: 10.2174/0929867053363243.
The matrix metalloproteinases (MMPs) are a family of more than 20 enzymes that are intimately involved in tissue remodelling. These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenase, stromelysins and gelatinases and are involved in the degradation of the extracellullar matrix (ECM) that forms the connective material between cells and around tissues. Disease processes associated with the MMPs are generally related to imbalance between the inhibition and activation of MMPs resulting in excessive degradation of the ECM. These indications include osteoarthritis rheumatoid arthritis, tumour metastasis and congestive heart failure. Inhibitors for these enzymes have been developed for the treatment of a starthingly wide array of disease process where matrix remodelling plays a key role. There are three major components to most MMP inhibitors- the zinc binding group ZBG, the peptidic backbone and the pocket occupying side chain. Most MMPs inhibitors are classified according to their ZBG. Inhibitors interactions at active-site zinc plays a critical role in defining the binding mode and relative inhibitor potency. The majority of MMP inhibitors reported in the literature contain an effective zinc binding group (e.g. hydroxamic acid, carboxylic acid, sulfhydryl group) that is either generally substituted with a peptide-like structure that mimics the substrates that they cleave or appended to smaller side chains that may interact with specific subsites (e.g., P1', P2', P3') within the active site. Although carboxylates exhibit weaker zinc binding properties than hydroxamates, they are known to show better oral bioavailability and are less prone to metabolic degradation. The expected loss of binding affinity after replacement of hydroxamates against carboxylates is faced by adequate choice of elongated S1' directed substituents. The need for novel selective MMP inhibitors makes them an attractive target for the QSAR and molecular modelling. 3-D QSAR models were derived using CoMFA, CoMSIA and GRID approaches leading to the identification of binding regions where steric, electronic or hydrophobic effects are important for affinity. Some structural requirements essential for achieving high binding affinity and selectivity are: an acidic unit tightly anchored through four contact points, bidentate chelation of Zn2+, carbonyl groups for hydrogen bonding, more than two extra units for hydrogen bonds, a hydrophobic moiety.
基质金属蛋白酶（MMPs）是一个由20多种酶组成的家族，它们与组织重塑密切相关。这些含锌的内肽酶由几个酶亚类组成，包括胶原酶、基质溶解素和明胶酶，参与细胞外基质（ECM）的降解，ECM构成细胞之间和组织周围的连接物质。与MMPs相关的疾病过程通常与MMPs抑制和激活之间的失衡有关，导致ECM过度降解。这些病症包括骨关节炎、类风湿性关节炎、肿瘤转移和充血性心力衰竭。已经开发出这些酶的抑制剂，用于治疗大量基质重塑起关键作用的疾病过程。大多数MMP抑制剂有三个主要成分——锌结合基团（ZBG）、肽主链和占据口袋的侧链。大多数MMP抑制剂根据其ZBG进行分类。抑制剂在活性位点锌处的相互作用在确定结合模式和相对抑制剂效力方面起着关键作用。文献中报道的大多数MMP抑制剂含有一个有效的锌结合基团（例如异羟肟酸、羧酸、巯基），该基团通常被类似肽的结构取代，该结构模拟它们切割的底物，或者连接到可能与活性位点内特定亚位点（例如P1'、P2'、P3'）相互作用的较小侧链上。虽然羧酸盐显示出比异羟肟酸盐弱的锌结合特性，但已知它们具有更好的口服生物利用度，并且更不易发生代谢降解。通过适当选择延长的S1'导向取代基，可以克服用羧酸盐替代异羟肟酸盐后预期的结合亲和力损失。对新型选择性MMP抑制剂的需求使它们成为定量构效关系（QSAR）和分子建模的有吸引力的目标。使用比较分子场分析（CoMFA）、比较分子相似性指数分析（CoMSIA）和GRID方法推导三维QSAR模型，从而确定空间、电子或疏水效应对于亲和力很重要的结合区域。实现高结合亲和力和选择性所必需的一些结构要求是：一个通过四个接触点紧密锚定的酸性单元、Zn2+的双齿螯合、用于氢键的羰基、超过两个用于氢键的额外单元、一个疏水部分。
