Abstract:
:Binding to the extracellular matrix, one of the most abundant human protein complexes, significantly affects drug disposition. Specifically, the interactions with extracellular matrix determine the free concentrations of small molecules acting in tissues, including signaling peptides, inhibitors of tissue remodeling enzymes such as matrix metalloproteinases, and other drug candidates. The nature of extracellular matrix binding was elucidated for 63 matrix metalloproteinase inhibitors, for which the association constants to an extracellular matrix mimic were reported here. The data did not correlate with lipophilicity as a common determinant of structure-nonspecific, orientation-averaged binding. A hypothetical structure of the binding site of the solidified extracellular matrix surrogate was analyzed using the Comparative Molecular Field Analysis, which needed to be applied in our multi-mode variant. This fact indicates that the compounds bind to extracellular matrix in multiple modes, which cannot be considered as completely orientation-averaged and exhibit structural dependence. The novel comparative molecular field analysis models, exhibiting satisfactory descriptive and predictive abilities, are suitable for prediction of the extracellular matrix binding for the untested chemicals, which are within applicability domains. The results contribute to a better prediction of the pharmacokinetic parameters such as the distribution volume and the tissue-blood partition coefficients, in addition to a more imminent benefit for the development of more effective matrix metalloproteinase inhibitors.
journal_name
Chem Biol Drug Desjournal_title
Chemical biology & drug designauthors
Zhang Y,Lukacova V,Bartus V,Nie X,Sun G,Manivannan E,Ghorpade SR,Jin X,Manyem S,Sibi MP,Cook GR,Balaz Sdoi
10.1111/j.1747-0285.2008.00710.xsubject
Has Abstractpub_date
2008-10-01 00:00:00pages
237-48issue
4eissn
1747-0277issn
1747-0285pii
JPP710journal_volume
72pub_type
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