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Evaluation of Rate Constants from Protein-Ligand Interactions with Weak Affinity Chromatography
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
2012 (English)Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
Abstract [en]

The paradigm of drug discovery have been to find the strongest possible binder to the target by high-throughput screening (HTS) but high affinity interactions are related to low kinetic off rates and thus result in severe side-effects and non-approved drugs. Lead molecules working in a transient manner (KD > µM) will allow for rapid off rates and possibly less side-effects. In this study the peak profile method applied to weak affinity chromatography (WAC) was evaluated as a simple way to provide the kinetics of the interaction and thereby allowing for high-throughput determinations. In the peak profile formula all band-broadening effects except the stationary mass transfer is subtracted which simplifies the calculations for the kinetics of the interaction tremendously. The technique was evaluated by screening of 3 different benzamidines at 3 linear flow-rates using zonal chromatography and human α-thrombin as immobilized target protein. The kinetics of the interaction could unfortunately not be determined. This was possibly due to the flow-rates not being high enough as indicated by a low critical ratio (η < 1). Higher flow-rates would increase the contribution to band-broadening due to kinetic effects but would also require more precise estimation of peak variance.

Place, publisher, year, edition, pages
2012. , 28 p.
Keyword [en]
peak profile method, dissociation / association rate constants, weak affinity chromatography, band-broadening
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-19974OAI: oai:DiVA.org:lnu-19974DiVA: diva2:533900
Subject / course
Chemistry
Educational program
Nutrition and Food Science Programme, 180 credits
Uppsok
Physics, Chemistry, Mathematics
Supervisors
Examiners
Available from: 2012-06-21 Created: 2012-06-14 Last updated: 2012-06-21Bibliographically approved

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Evaluation of Rate Constants from Protein-Ligand Interactions with Weak Affinity Chromatography(1120 kB)1056 downloads
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CiteExportLink to record
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