Maps of where small chemical fragments and waters bind to proteins, derived from simulations (Boltzmann Maps), have been productively employed in dozens of successful drug lead projects. In such projects, maps are interrogated to generate ideas for novel lead compounds and prioritize them for progression. Unfortunately, such maps have only been available as proprietary technology at a handful of companies, due to the operational complexity and computational cost of producing the maps on a large scale. Boltzmann Maps are now being made broadly available (www.boltzmanmaps.com) at low cost through a cloud-hosted Web application, BMaps. We will discuss the challenges in generating, delivering, and using Boltzmann Maps, and how they are addressed in the BMaps Web application. To support fragment-based design, lead modifications can be explored with fragment growing using maps, prioritized with a free energy metric (excess chemical potential). Chemist’s ideas can be sketched and then evaluated by protein-compound interaction energies and △△G<sub>s</sub> desolvation costs. Rigorously derived water maps, highlighted by affinity, can provide key insights as to the impact of bound waters on lead compound binding. While 100s of fragment and water maps for about 500 important protein targets have been pre-computed, a noteworthy development is the ability to run water or fragment simulations on most structures downloadable from the PDB with a very simple interface. The BMaps Web application has the potential to become a key tool for drug discovery, widely available to drug researchers. Finally, we will present data on a fragment-based discovery project that led to novel fragments and small molecules for disrupting PCSK9 binding to LDLR.

BMaps: New web application for structure and fragment-based drug design using Boltzmann maps

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.