The thermodynamic and kinetic constants of a protein-ligand complex describe in full its macroscopic behavior. However, they say very little about the events that occur at the atomic level. In consequence, the thermodynamic and kinetic measurements can be used to prioritize compounds, but cannot guide ligand optimization unless a relationship can be established between these macroscopic observables and the microscopic processes. In this context, it is important to understand the nature of proteins, which impose certain additional restrictions to the complexes they form. For instance, while the binding free energy (?Gbind) might theoretically emerge from a sum of equally important interactions, in fact proteins present privileged binding sites, the so-called hot spots. Hot spots can be accurately predicted and this information can be used to predict druggability or to obtain accurate interaction maps that facilitate ligand discovery.1,2 Equally, the transition state, which determines the kinetic parameters, could be theoretically located anywhere between the bound and unbound states. But here we demonstrate that true ligands encounter a high barrier early in the dissociation process, which is largely due to water-shielded hydrogen bonds 3 and influences the transition state. Indeed, the structural stability of the binding mode implies that it is located in a deep and narrow minimum in the free energy landscape. This information can be used very effectively in virtual ligand screening.4 (1) Seco, J.; Luque, F. J.; Barril, X. J. Med. Chem. 2009, 52 (8), 2363. (2) Alvarez-Garcia, D.; Barril, X. J. Med. Chem. 2014, 57 (20), 8530. (3) Schmidtke, P.; Luque, F. J.; Murray, J. B.; Barril, X. J. Am. Chem. Soc. 2011, 133 (46), 18903. (4) Ruiz-Carmona, S.; et al. Submitted. 2015

Kinetic stability of protein-ligand complexes: Applications in virtual screening

251st National Meeting (2016)

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