Selective Inhibitors of Medium-Size S1′ Pocket Matrix Metalloproteinases: A Stepping Stone of Future Drug Discovery

Abstract

Among various matrix metalloproteinases (MMPs), MMPs having medium-size S1′ pockets are established as promising biomolecular targets for executing crucial roles in cancer, cardiovascular diseases, and neurodegenerative diseases. However, no such MMP inhibitors (MMPIs) are available to date as drug candidates despite a lot of continuous research work for more than three decades. Due to a high degree of structural resemblance among these MMPs, designing selective MMPIs is quite challenging. However, the variability and uniqueness of the S1′ pockets of these MMPs make them promising targets for designing selective MMPIs. In this perspective, the overall structural aspects of medium-size S1′ pocket MMPs including the unique binding patterns of enzyme−inhibitor interactions have been discussed in detail to acquire knowledge regarding selective inhibitor designing. This overall knowledge will surely be a curtain raiser for the designing of selective MMPIs as drug candidates in the future.

Role of metalloproteases in the CD95 signaling pathways

“…Beside their poor pharmacokinetics and low oral availability/inability, this major failure has been mainly attributed to their lack of specificity within the MMP family and towards other metalloenzymes. Benefiting from a better understanding of MMP biology that emphasizes the necessity to selectively target one single MMP in a given pathological context, a new generation of selective MMPi has emerged recently ( 131 ). To achieve a better selectivity, several strategies have been deployed.…”

“…To achieve a better selectivity, several strategies have been deployed. Regarding the small-molecule inhibitors they mainly consist in either replacing the hydroxamic acid group found in most of broad spectrum MMPis by a weaker Zn 2+ chelating moiety ( 132 , 133 ) or targeting exclusively the S1’ pocket which significantly differ between the MMPs ( 131 , 132 ). Alternatively, the development of surrogates of MMPs endogenous inhibitors such as TIMP analogs or targeting MMP gene expression using mRNAs have also been explored.…”

Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase-2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold

“…Indeed, the small-molecule MMP inhibitors tested in clinical trials have shown uncertain efficacy and various side effects due to their poor selectivity. For this reason, selective MMP inhibitors have been actively investigated in recent years. − Because the depth of the S1′ pocket differs among MMP subtypes, suitable S1′ pocket-binding groups for each subtype have been explored for MMP selectivity. − …”

Quantitative structural assessments of potential meprin β inhibitors by non-linear QSAR approaches and validation by binding mode of interaction analysis

“…The study of the metalloenzymes in normal and pathophysiological conditions has elucidated several crucial involvements of these enzymes in a wide range of disease states, including cancer, neurodegenerative disorders, inflammation, osteoarthritis, cardiovascular diseases, viral and parasitic infections, as well as in epigenetic abnormalities. [1][2][3][4][5][6][7] Although several attempts were made to develop potential and selective inhibitors of such metalloenzymes, a few novel molecules have been approved to date for targeting such metalloenzyme-related pathophysiology and associated disease conditions. 8 Among these metalloenzymes, the Zn 2+ -dependent metalloenzyme meprin b is one of the metzincin superfamily proteases that modulates several substrates such as procollagen I, collagen IV, triggered receptor expressed on myeloid cells 2 (TREM 2), interleukin (IL)-6R, cluster of differentiation (CD) 109, CD99, MUC-2, amyloid precursor protein (APP), E-cadherin, and IL-1b.…”

“…The study of the metalloenzymes in normal and pathophysiological conditions has elucidated several crucial involvements of these enzymes in a wide range of disease states, including cancer, neurodegenerative disorders, inflammation, osteoarthritis, cardiovascular diseases, viral and parasitic infections, as well as in epigenetic abnormalities. 1–7 Although several attempts were made to develop potential and selective inhibitors of such metalloenzymes, a few novel molecules have been approved to date for targeting such metalloenzyme-related pathophysiology and associated disease conditions. 8…”