Abstract
BackgroundThe discovery and development of anticancer still remain a challenge especially regarding the problem of cancer cell selectivity. Matrix metalloproteinase (MMP) was broadly studied as one of the protein targets to stop cancer angiogenesis as well as its cell migration.Main textThe MMP degrades extracellular matrix (ECM) such as collagen and gelatin which are important to control the cell migration from one to other sites. In cancer, this cell migration is regarded with metastasis, which is essential for the formation of new blood vessels called angiogenesis. The most common target in MMP, i.e. the catalytic site, is currently reported as being the non-selective target for inhibitor compounds that inhibit all MMPs but is associated with adverse side effects. Hemopexin, especially in MMP9 (PEX9) was found to be different from other domains in the MMP family which could potentially be the next target for anticancer due to the availability of its crystal structure in the Protein Data Bank (PDB).ConclusionThe PEX9 crystal structure was resolved as a homodimer connected by a hydrophobic area between two blades along the β-propeller which its structure and function for computational drug modelling can be studied.
Highlights
The Matrix metalloproteinase (MMP) degrades extracellular matrix (ECM) such as collagen and gelatin which are important to control the cell migration from one to other sites
The dimer is connected by the hydrophobic area between each blade 4 along the β-propeller forming the structure as an assymmetric plane [70]. Two studies utilised this crystal structure as the model in a virtual screening of the ZINC database in the effort to discover MMP9 inhibitors which can selectively bind to the PEX domain, as explained below
A potential compound from the ZINC database bearing a pyrimidinone scaffold extended by an arylamide moiety connected with a flexible S-alkyl chain was used to identify the pharmacophore which meets the requirements to be active as a PEX9 inhibitor
Summary
The MMP degrades extracellular matrix (ECM) such as collagen and gelatin which are important to control the cell migration from one to other sites. In cancer, this cell migration is regarded with metastasis, which is essential for the formation of new blood vessels called angiogenesis. The most common target in MMP, i.e. the catalytic site, is currently reported as being the non-selective target for inhibitor compounds that inhibit all MMPs but is associated with adverse side effects. Especially in MMP9 (PEX9) was found to be different from other domains in the MMP family which could potentially be the target for anticancer due to the availability of its crystal structure in the Protein Data Bank (PDB)
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