Computational Structural Biology in Modern Integrative Discovery Pipelines

Abstract

Computational structural biology (CSB) and computer-aided drug design enable research and discovery pipelines that drive scientific innovation. The integration between development of CSB pipelines, application of state-of-the-art methods, and experimental collaboration constitute the current, modern paradigm in drug development. Emerging and rapidly developing fields in drug discovery involve novel classes of small molecule therapeutics that escape the boundaries of classical inhibition mechanisms. In this context, Proteolysis Targeting Chimeras (Protacs) are a promising drug modality of bifunctional compounds that promote the degradation of a protein of interest by triggering endogenous ubiquitin-proteasome signalling. In addition, protein-protein and protein-peptide interface design are methods central to state-of-the-art protein engineering campaigns. Extreme throughput mutagenesis through computational modelling enables the vast exploration required for true novelty in fields such as inhibitor design, antibody-antigen recognition, and specificity and affinity engineering. This work presents novel tools and scientific findings in a research model that follows the state-of-the-art CSB paradigm of integrative development, application, and experimental collaboration. We present a fully automated and accurate Protac ternary complex modelling platform; an extreme high-throughput interface mutagenesis tool to scan tens of millions of mutants in a physics-informed manner; and an automated molecular dynamics pipeline that introduces a unique, truly gentle protocol for system equilibration. In turn, these tools were applied to research questions involving prominent disease targets to guide posterior experimental efforts or explain previous experimental findings. The work presented in this thesis also provides a framework for understanding CSB's ever growing place of importance in current innovative scientific research.