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Energetics of Drug Interactions

dc.contributor.advisorKelman, Zvien_US
dc.contributor.advisorSchwarz, Frederick P.en_US
dc.contributor.authorTodorova, Niya Anchevaen_US
dc.date.accessioned2009-01-24T06:56:39Z
dc.date.available2009-01-24T06:56:39Z
dc.date.issued2008-11-26en_US
dc.identifier.urihttp://hdl.handle.net/1903/8800
dc.description.abstractThe goal of our research is to determine in terms of thermodynamic change of state functions the effects of experimental factors, such as water, mutagenesis, or the presence of a second substrate on the energetics of drug-inhibitor binding interactions. The binding of non-steroidal anti-inflammatory drugs within the rigid cavities of cyclodextrins was investigated by titration calorimetry and spectrofluorimetry. Loss of bulk water structure upon drug binding in the smaller hydrophobic β-cyclodextrin cavity results in an increase in the binding entropy, while restriction of the configurations of the drug in the cavity decreases the binding entropy. This restriction in the hydrophobic β-cyclodextrin cavity enhances the binding enthalpies so that the β-cyclodextrin binding reactions are enthalpy-driven. In the larger γ-cyclodextrin cavity, water is retained so that, not only are the interactions between the drug and the cavity reduced, there is an increase in the drug configurations resulting in increases in the binding entropies and the binding reactions become entropically-driven. These binding reactions also manifest enthalpy-entropy compensation where changes in the binding enthalpies are compensated by changes in the binding entropies. In drug binding to the more flexible p38α MAP kinase mutants, a single-point C→S mutation distal from the binding site, changes the interaction between the N- and C-terminal structural domains of the kinase as evident in differential scanning calorimetry. Calorimetric results show that drug-inhibitor binding affinities to kinase increase with size of the drugs since the binding reactions are all enthalpically-driven. Drug-inhibitors binding to trimeric human purine nucleoside phosphorylase were investigated by calorimetry in the presence of its second substrate, inorganic phosphate (Pi). Increasing concentrations of Pi modulates the driving-nature of the binding reaction, so that the acyclovir binding almost exclusively to the purine substrate binding site becomes more entropically-driven, while the binding reactions of ganciclovir and 9-benzylguanine interacting also with the adjacent Pi substrate site become more enthalpically-driven. A novel calorimetric enzyme activity assay at the low dissociation concentrations of the phosphorylase show an increase in the enzyme activity at low Pi concentrations, but also a decrease in the 9-benzylguanine binding affinity since this drug also interacts with an adjacent subunit.en_US
dc.format.extent3469343 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.titleEnergetics of Drug Interactionsen_US
dc.typeDissertationen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.contributor.departmentMolecular and Cell Biologyen_US
dc.subject.pqcontrolledChemistry, Biochemistryen_US
dc.subject.pqcontrolledBiophysics, Generalen_US
dc.subject.pquncontrolleddrug-inhibitoren_US
dc.subject.pquncontrolledproteinen_US
dc.subject.pquncontrolledinteractionsen_US


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