Fragment-based drug discovery (FBDD) is an effective approach for exploring chemical space using small, low-affinity fragments as starting points to facilitate development of lead compounds. Strategies to improve fragment potency include fragment merging and linking to generate higher-affinity inhibitors. Recently, artificial intelligence (AI) and machine learning (ML) have accelerated this process through structure-based optimization and generative compound design. Here, we present an AI-assisted FBDD workflow applied to the SARS-CoV-2 macrodomain (Mac1), a conserved viral protein involved in immune evasion and ADP-ribose metabolism. Using available structural data and previously identified fragments, we combined deep learning with molecular docking to design novel Mac1 binders. Selected compounds were synthesized and validated by NMR spectroscopy and X-ray crystallography, demonstrating improved binding relative to the original fragment hits with KD values in the range of 299-990 µM. This study demonstrates the advantages of integrating AI with FBDD to streamline molecular design, providing a data-driven framework for discovering new Mac1 inhibitors and guiding future antiviral drug development.
Elnaz Aledavood, Sandra Ramos-Inza, Jannis Born et al.· Communications Chemistry· 0 citations
Transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Modulation of TDP-43 pathology represents a promising disease-modifying strategy. Tau tubulin kinase 1 (TTBK1) has emerged as a relevant therapeutic target; however, selectivity over the TTBK2 isoform is required to avoid ciliogenesis-related liabilities. Here, we report the discovery of selective, brain-penetrant TTBK1 inhibitors through a structure-guided medicinal chemistry program. Lead compounds exhibit potent and selective TTBK1 inhibition, no impact on ciliogenesis, and central nervous system exposure. We found that these inhibitors reduce TDP-43 phosphorylation levels in neuroblastoma cells and FTD patient-derived models. The optimized lead compound demonstrated a brain-to-plasma ratio of 3:1, a maximum tolerated dose, and a wide therapeutic window. In vivo, administration restored cognitive deficits, conferred neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model, supporting its therapeutic potential.
Cecilia Sanchez-Santos, Alberto Jiménez-Amor, Loreto Martínez-González et al.· Journal of Medicinal Chemist...· 0 citations