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High-Throughput Methods to Determine Intermolecular Association and Lipophilicity

Chen, Zhi (2007) High-Throughput Methods to Determine Intermolecular Association and Lipophilicity. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Noncovalent intermolecular associations are omnipresent in chemical and biochemical systems. Binding constants provide a fundamental measure of the affinity of a solute to a ligand; hence their determination has been an important step in describing and understanding molecular interactions. A high-throughput method based on the concept of phase distribution has been developed to determine binding constants. The solute distribution coefficients between a polymer phase and an aqueous phase are measured in a 96-well format, in the presence and absence of the ligand in one of the two phases. Binding constants are then calculated through linear or nonlinear fitting analyses. The polymer is plasticized poly(vinyl chloride). This high-throughput approach has been employed in several applications. In the first one, the partition ratios (no ligand in either phase) of neutral solutes have been correlated with their lipophilicities (octanol-water partition coefficients). The established linear correlation between their logarithmic values can be used as a calibration curve to predict the lipophilicity of compounds with unknown lipophilicity values. The pKa value of a charged compound and the distribution coefficient of the ionic form can also be determined by this approach. In the second application, binding constants in the film phase have been determined for the fast evaluation of enantioselectivity of potential chiral selectors. The technique identified one chiral selector for the target econazole from a small library of twelve cyclopropyl dipeptide isosteres. Compared to other screening approaches, this protocol does not require the covalent attachment of either the target of the selector candidate hence decreases the time and labor required for screening. In addition, the amount of the potential chiral selector (~100 µg) needed is significantly reduced. Similarly, intermolecular association can be determined in the aqueous phase. In the last application, binding constants of drug-cyclodextrin complex formation have been measured at various cyclodextrin concentration and pH conditions with various cyclodextrins. Again, high throughput and low mass requirement are advantages of the method.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Chen, Zhizhc3@pitt.eduZHC3
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWeber, Stephen Gsweber@pitt.eduSWEBER
Committee MemberDay, Billybday@pitt.eduBDAY
Committee MemberAmemiya, Shigeruamemiya@pitt.eduAMEMIYA
Committee MemberPetoud, Stephanespetoud@pitt.eduSPETOUD
Date: 29 June 2007
Date Type: Completion
Defense Date: 23 April 2007
Approval Date: 29 June 2007
Submission Date: 23 April 2007
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Binding Constant; Chirl Selector; Cyclodextrin; Lipophilicity; Intermolecular Association; Solid Phase Microextraction; High-Throughput; Phase Distribution
Other ID:, etd-04232007-180716
Date Deposited: 10 Nov 2011 19:41
Last Modified: 15 Nov 2016 13:42


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