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ACS Biomaterials Science & Engineering Mar 2017Glioblastoma multiforme patients suffer a median survival of 14 months, facilitated by the highly invasive nature of this cancer that allows for it to evade conventional...
Glioblastoma multiforme patients suffer a median survival of 14 months, facilitated by the highly invasive nature of this cancer that allows for it to evade conventional therapy. Prinomastat targets the essential matrix metalloproteinase degradation of the extracellular matrix needed for cancer invasion; however, its clinical potential is impeded by adverse musculoskeletal side effects. By localizing delivery of prinomastat via cyclodextrin polymers, systemic side effects can be bypassed. In this letter, we demonstrate that prinomastat delivery from β-cyclodextrin polymers results in months-long inhibition of MMPs as measured by gelatin zymography, more appropriately addressing the time frame of cancer cell invasion.
PubMed: 33465922
DOI: 10.1021/acsbiomaterials.6b00626 -
The Journal of Biological Chemistry Feb 2015P450 2D6 contributes significantly to the metabolism of >15% of the 200 most marketed drugs. Open and closed crystal structures of P450 2D6 thioridazine complexes were...
P450 2D6 contributes significantly to the metabolism of >15% of the 200 most marketed drugs. Open and closed crystal structures of P450 2D6 thioridazine complexes were obtained using different crystallization conditions. The protonated piperidine moiety of thioridazine forms a charge-stabilized hydrogen bond with Asp-301 in the active sites of both complexes. The more open conformation exhibits a second molecule of thioridazine bound in an expanded substrate access channel antechamber with its piperidine moiety forming a charge-stabilized hydrogen bond with Glu-222. Incubation of the crystalline open thioridazine complex with alternative ligands, prinomastat, quinidine, quinine, or ajmalicine, displaced both thioridazines. Quinine and ajmalicine formed charge-stabilized hydrogen bonds with Glu-216, whereas the protonated nitrogen of quinidine is equidistant from Asp-301 and Glu-216 with protonated nitrogen H-bonded to a water molecule in the access channel. Prinomastat is not ionized. Adaptations of active site side-chain rotamers and polypeptide conformations were evident between the complexes, with the binding of ajmalicine eliciting a closure of the open structure reflecting in part the inward movement of Glu-216 to form a hydrogen bond with ajmalicine as well as sparse lattice restraints that would hinder adaptations. These results indicate that P450 2D6 exhibits sufficient elasticity within the crystal lattice to allow the passage of compounds between the active site and bulk solvent and to adopt a more closed form that adapts for binding alternative ligands with different degrees of closure. These crystals provide a means to characterize substrate and inhibitor binding to the enzyme after replacement of thioridazine with alternative compounds.
Topics: Catalytic Domain; Crystallography, X-Ray; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Humans; Hydrogen Bonding; Molecular Dynamics Simulation; Organic Chemicals; Secologanin Tryptamine Alkaloids
PubMed: 25555909
DOI: 10.1074/jbc.M114.627661