<br/>Structure-based drug design has been a centerpiece of drug discovery and its extensive use has underpinned a better understanding of small-molecule-protein interactions. From the computational chemistry perspective, protein-ligand structures provide excellent starting points to begin new drug discovery projects. It is likely that at the start of a project only the snapshots of protein geometries provided by one or two structures are available. While very helpful in the discovery process, these limited examples are insufficient to predict significant protein motion and using iterative protein structure determination for early drug discovery is a fairly expensive approach. With the advent of GPU-based computing, large time-scale (1000 nsec) simulations are now practical due to the modest cost of hardware and the availability of open-source software. I will review several drug discovery projects where, prior to the current accessibility of large time-scale simulations, protein and solvent motion hampered our ability to resolve the uncertainties of protein-ligand geometries. Yet, at the time of execution of these projects, we were able to contribute useful models that led to new inventions. Projects involving ligand-mediated protein-protein interaction (RBP4), agonists-antagonists transitions (glucocorticoid receptor) and bromodomains will be considered. We will illustrate some of the simple approaches we used, where they were useful, and where the accuracy was suspect. At the time, we were aware that the models were limited simply due to the impracticality of performing MD simulations within the project timelines. Now, using GPU-based calculations, long MD simulations can sample macromolecular systems to identify large backbone changes in a matter of days of computation, providing the possibility of multiple, realistic binding site models in a useful timeframe. We will present a retrospective analysis of these binding sites using moderate length MD simulations to see where these calculations provide support for better insights into protein-ligand interactions and improved models for early drug discovery projects.

Examples and new capabilities to account for protein movement in early drug discovery

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.