A considerable number of approved drugs show non-equilibrium binding characteristics, emphasizing the potential role of drug residence times for in vivo efficacy. Therefore, a detailed understanding of the kinetics of association and dissociation of a target-ligand complex might provide crucial insight into the molecular mechanism-of-action of a compound. This deeper understanding will help to improve decision making in drug discovery, thus leading to a better selection of interesting compounds to be profiled further. In this review, we highlight the contributions of the Kinetics for Drug Discovery (K4DD) Consortium, which targets major open questions related to binding kinetics in an industry-driven public-private partnership.
Computational
approaches currently assist medicinal chemistry through
the entire drug discovery pipeline. However, while several computational
tools and strategies are available to predict binding affinity, predicting
the drug–target binding kinetics is still a matter of ongoing
research. Here, we challenge scaled molecular dynamics simulations
to assess the off-rates for a series of structurally diverse inhibitors
of the heat shock protein 90 (Hsp90) covering 3 orders of magnitude
in their experimental residence times. The derived computational predictions
are in overall good agreement with experimental data. Aside from the
estimation of exit times, unbinding pathways were assessed through
dimensionality reduction techniques. The data analysis framework proposed
in this work could lead to better understanding of the mechanistic
aspects related to the observed kinetic behavior.
Residence time and more recently the association rate constant k are increasingly acknowledged as important parameters for in vivo efficacy and safety of drugs. However, their broader consideration in drug development is limited by a lack of knowledge of how to optimize these parameters. In this study on a set of 176 heat shock protein 90 inhibitors, structure-kinetic relationships, X-ray crystallography, and molecular dynamics simulations were combined to retrieve a concrete scheme of how to rationally slow down on-rates. We discovered that an increased ligand desolvation barrier by introducing polar substituents resulted in a significant k decrease. The slowdown was accomplished by introducing polar moieties to those parts of the ligand that point toward a hydrophobic cavity. We validated this scheme by increasing polarity of three Hsp90 inhibitors and observed a 9-, 13-, and 45-fold slowdown of on-rates and a 9-fold prolongation in residence time. This prolongation was driven by transition state destabilization rather than ground state stabilization.
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