Ultralarge virtual screenings (ULVSs) evaluate billions of molecules for drug discovery but face cost, flexibility and scalability limits. We introduce AdaptiveFlow, an open-source platform that makes ULVSs more accessible, scalable and efficient and supports artificial intelligence (AI) and machine learning (ML) method development. AdaptiveFlow provides a screening-ready version of the Enamine REAL Space, to our knowledge the largest library of ready-to-dock, drug-like molecules, comprising 69 billion compounds, also available in SELFIES format. An 18-dimensional grid of molecular properties prioritizes promising chemical subspaces, with optional active learning, reducing computational costs by orders of magnitude. AdaptiveFlow integrates >1,500 docking protocols, including GPU-accelerated and ML-based methods, and achieves near-linear scaling on up to 5.6 million CPUs in the Amazon Web Services cloud. We identified nanomolar inhibitors of two disease-relevant targets, ferroptosis suppressor protein 1 (FSP1) and poly(ADP-ribose) polymerase 1. Co-crystal structures provided mechanistic insights into FSP1 inhibition. AdaptiveFlow enables drug discovery at unprecedented scale and supports the development of AI-driven methods.
Domiziana Cecchini, AkshatKumar Nigam, Ming Tang et al.· Nature Biotechnology· 0 citations
IL4I1, a human L-amino acid oxidase (LAAO), has drawn considerable interest for its role in catabolism with implications for cancer biology and immune modulation. The function and activity of this enzyme in humans contrast with the cytotoxic effects exerted by LAAOs from snake venoms. The inherent instability of IL4I1 has hindered detailed biochemical characterization and its exploration as a drug target. In this study, we present a comprehensive biochemical and structural investigation of tetrapod LAAOs, with a focus on human IL4I1 and its evolutionary relationship to venomous snake proteins. By exploiting ancestral sequence reconstruction, we inferred, expressed, and characterized the tetrapodal ancestral LAAO and mammalian ancestral IL4I1 and compared their properties to recombinant human IL4I1 purified from human cells. The tetrapodal ancestor displays a broad substrate profile, acting on hydrophobic, polar, and positively charged amino acids, whereas human IL4I1 prefers aromatic amino acids. Guided by crystal structures, we engineered eight ancestral protein variants to mimic mammalian- and snake-like active site configurations. Kinetic analyses of these variants reveal distinct evolutionary trajectories: one leading to the high-activity venomous LAAOs of reptiles, and another to the aromatic-selective IL4I1 of mammals. Overall, our findings demonstrate that the functional divergence between human IL4I1 and venomous snake LAAOs is underpinned by evolutionary shifts in substrate specificity and catalytic efficiency.
Marta Massari, Jonatan Caroli, Marco Malatesta et al.· Proceedings of the National...· 0 citations
Compound 5, although aqueous solubility issues limited its cellular antiproliferative performance, represents a specific, artifact-free architectural starting point for future selective NOX inhibitor development.
Emanuele Fabbrizi, Andrea Mancini, Chiara Lambona et al.· ACS Medicinal Chemistry Lett...· 0 citations
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