Matrix metalloproteinase inhibitors: a review on pharmacophore mapping and (Q)SARs results

Abstract

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.