Presenter: Benjamin P. Brown (Vanderbilt University School of Medicine)
Topic: Designing a customizable platform for small molecule drug design compatible with protein flexibility and sequence design
Computer-aided drug design (CADD) has become a core component of modern drug discovery. Today, multiple algorithms have emerged that facilitate the exploration of druglike chemical space: one-shot made-on-demand reaction-based design, generative machine learning models, and rapid combinatorial chemistry are all important advancements in the exploration of chemical space. Despite these advancements, drug design projects frequently require a level of adaptability not provided by individual standalone software packages. This is particularly noteworthy for drug design tasks involving highly flexible proteins, induced-fit drug design, and simultaneous sequence design (e.g., chemogenetics design). To address these limitations, we have integrated the BioChemical Library (BCL) cheminformatics toolkit with the Rosetta macromolecular modeling suite and written a series of drug design “mutates”. These mutates can perform one-shot made-on-demand style reactions, single- and multi-component reactions, or reaction-free medicinal chemistry-inspired “alchemical” perturbations. Our work represents a new, highly customizable drug design framework that is extensible to emerging therapeutic modalities.