title: Structural determinants of binding of aromates to extracellular matrix: a multi-species multi-mode CoMFA study.
abstract: For small molecules acting in tissues, including signaling peptides, effectors, inhibitors, and other drug candidates, nonspecific binding to the extracellular matrix (ECM) is a critical phenomenon affecting their disposition, toxicity, and other effects. A commercially available ECM mimic, forming a solidified layer at the bottom of the vials, was used to measure the association constants of 25 simple aromatic compounds to two forms of ECM proteins, solidified (s-ECM) and dissolved (d-ECM) in the buffer during the incubation. Except for small homologous series, the binding data did not correlate with the lipophilicity and acidity of the compounds, contrary to a common expectation for nonspecific binding. To elucidate the putative structures of averaged binding sites of s-ECM and d-ECM, comparative molecular field analysis (CoMFA) was applied in a modified version taking into consideration that multiple modes and multiple species may be involved. The method shapes a receptor site model from a set of grid points in which the interaction energies between a probe atom and superimposed ligands are calculated. Electrostatic and steric energies in the grid points are characterized by regression coefficients. The forward-selection nonlinear regression analysis was used to optimize the coefficients in the novel multi-species, multi-mode CoMFA models. These models showed satisfactory descriptive and predictive abilities for both s-ECM and d-ECM binding data, which were better than those obtained with the standard, one-mode CoMFA analysis. The calibrated models, defining the electrostatic and van der Waals regions of putative binding sites, are suitable for the prediction of ECM binding for untested chemicals.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota 58105.
authors.forename: Yufen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Viera
authors.initials: V
authors.lastname: Lukacova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bartus
authors.forename: Stefan
authors.initials: S
authors.lastname: Balaz
mesh_terms: D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D055672:Static Electricity
chemical_list: D016326:Extracellular Matrix Proteins; D008024:Ligands