Thermodynamics reign in drug discovery and binding affnity optimization, even though kinetic aspects are central and would provide a more detailed vision of the binding process [Holdgate and Ward, 2005, Swinney, 2009, Englert
et al., 2010].

David C Swinney, a pioneer in promoting the importance of binding kinetics in drug discovery describes the current situation in the following poignant terms:
"Current capabilities for the use of binding kinetics in shaping and eecting safe, therapeutic responses are rudimentary. There is a lack of understanding or awareness that binding kinetics can be used to dierentiate drugs, as well as a lack of appreciation that the optimization of binding kinetics and mechanisms can drive an increase in the therapeutic index of a drug. Furthermore, the application of binding kinetics as a discovery and optimization parameter currently requires an empirical approach due to the challenge of employing this reductionist biochemical tool to complex physiological systems."

In several studies Swinney shows the potential of considering kinetics in particular in addition to the understanding of underlying mechanisms of action [Swinney and Anthony, 2011] to dene drug efficacy, safety, duration of action and dierentiation to other medicines. This eort is supported by Copeland [Copeland et al., 2006] and Zhang [Zhang and Monsma, 2009], focusing particularly on the eect of long residence times of drug molecules in their respective binding sites, directly linked to the duration of action and thus pharmacokinetic proles, target selectivity and drug safety. The importance of residence time was already acknowledged very early in a study by Leysen and Gommeren on serotonin-S2, dopamin-D2 and histamin-H1 antagonists and opiates[Leysen and Gommeren, 1986]. In the context of increasing importance and possibilities in systems biology approaches Ohlson shows the putative interest of transient drugs, characterised by fast o and on rates [Ohlson, 2008]. Despite these contributions, the pharmaceutical industry "still appears to be acting with trepidation toward assessing the fundamental role of kinetics in drug actions" [Zhang and Monsma, 2009]. Reasons for this hesitating behaviour of industry can be manifold, but a central aspect is the lack of understanding of binding kinetics and the lack of known structural characteristics on the ligand and receptor site influencing kinetics. We are investigating the structural determinants of binding kinetics to help bridging this gap.

Recently, we have published a paper (http://dx.doi.org/10.1021/ja207494u) where water-shielded hydrogen bonds are identified as kinetic traps in protein-ligand binding.