The Use of Structural Information to Understand Binding Kinetics
Felix Schiele, Pelin Ayaz, Anke Müller‐Fahrnow · Methods and principles in medicinal chemistry · 2015
Rational optimization of binding kinetics has moved into the focus of attention since the importance for drug efficacy as well as safety is more and more acknowledged. Two main routes are pursued to better understand and predict binding kinetics. At the moment, the comparison of apo and complex crystal structures is the favored approach. In combination with kinetic data, this strategy might be sufficient to deduce the effect of most individual atomic interactions. Identifying atomic interactions along the binding pathways that influence transition and ground state energies is the second route. Structural observation of very short lived transition states is argued to be the key in this respect. Methods such as binding IE measurements, time-resolved Laue X-ray crystallography, and molecular dynamics simulations still have to be assessed for this purpose. Kinetic rate optimization is not straightforward, as our understanding of the structural features that drive kinetic properties is still limited.