The Kinetics and Thermodynamics of
            <i>Staphylococcus aureus</i>
            FabI Inhibition

Chang, Andrew; Kapilashrami, Kanishk; Allen, Eleanor K. H.; Tonge, Peter J.

doi:10.1002/9783527673025.ch15

Cited by 1 publication

(1 citation statement)

References 62 publications

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“…Additional structural information gained by biophysical methods (x-ray crystallography; nuclear magnetic resonance (NMR) and molecular dynamics simulation) can help to expand our knowledge about structure-kinetic relationships. Most frequently, the drug bound target structure is compared to the apo target structure, while taking the kinetic rate constants into account (134). As an alternative, relaxation dispersion NMR spectroscopy allows for tracking of protein-folding at a millisecond time resolution.…”

Section: Structure-based Analysismentioning

confidence: 99%

Binding kinetics in drug discovery ndash A current perspective

et al. 2017

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The impact of target binding kinetics (BK) on the clinical performance of therapeutic agents is presently a topic of intense debate in drug discovery. While retrospective studies suggest that BK is a differentiating parameter in marketed medicines, it is yet unclear how this information could be used to prioritize drug candidates during lead optimization. Motivated by the question whether BK can be understood and rationally optimized, we review the most relevant literature in the field, with special focus on selected examples from our organization. First we discuss structure-kinetic relationships (SKR), and how they can be influenced by factors such as conformational changes, molecular flexibility, hydrogen bonds, hydrophobicity, water molecules and (reversible-) covalent bonds. We then introduce the methodologies currently used for the investigation of BK parameters, briefly commenting on their strengths, weaknesses and future trends. Finally, we present our current perspective on the integration of BK in the drug discovery process, aiming to stimulate further thoughts on this important subject.

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Section: Structure-based Analysismentioning

confidence: 99%