In recent years, the impact of the lifetime of the binary drug target complex (residence time) on drug efficacy and safety has been increasingly acknowledged. However, a broader consideration of kinetic parameters in the lead-optimization process has been impeded by the lack of structure kinetic relationship (SKR) understanding. This has prompted public-private entities such as the IMI with its K4DD project, as well as research groups to kinetically characterize small molecule binding to drug targets. In our study we aim to collect and centralize these kinetic datasets to make them amenable to large scale data analysis. In detail, we merged kinetic datasets from 20 publications with the K4DD (Kinetics for Drug Discovery) database to obtain a fused dataset of approximately 4000 data triplets (kon, koffand KDvalues per observation) derived from various protein classes (GPCRs: 273, Kinases: 3238, Other enzymes: 240, HSPs: 160, Ion Channels: 45). To maintain high practicability of our analysis for the medicinal chemist, we opted for matched molecular pairs (MMPs) analysis to investigate the structure kinetic relationship in our data collection. This returned 404 matched molecular pairs with their respective differences in kon, koffand KDvalues. We observed that in accordance to the findings of Schuetz et al.1, polar substituents tend to slow down the association rate constant. However, we also observed that the destabilization of the transition state introduced by polar substituents is often accompanied by a simultaneous destabilization of the ground state resulting in unaffected or even worsened residence time. Subsequently, we extended our studies to include pocket information to the matched pair analysis (MMP). Operating with GRID to describe the topology of subpockets allowed to develop a new, two-sided approach. This more complete perspective might identify the preconditions for polar substituents to achieve both, transition state destabilization and simultaneous ground state stabilization, thus leading to a scheme to effectively steer residence time in the context of lead-optimization.

Combining matched molecular pairs with binding pocket analysis to gain new insights into molecular features driving drug binding kinetics

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.