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Kostiantyn Lapchevskyi

Alumni

Publications

Generative Active Learning for the Search of Small-Molecule Protein Binders
Maksym Korablyov
Cheng-Hao Liu
Moksh Jain
Almer Van Der Sloot
Éric Jolicoeur
Edward Ruediger
Andrei Nica
Emmanuel Bengio
Kostiantyn Lapchevskyi
Daniel St-Cyr
Doris Alexandra Schuetz
Victor Ion Butoi
Jarrid Rector-Brooks
Simon Blackburn
Leo Feng
Hadi Nekoei
Saikrishna Gottipati
Priyesh Vijayan
Prateek Gupta
Ladislav Rampasek … (voir 14 de plus)
Sasikanth Avancha
Pierre-Luc Bacon
William Hamilton
Brooks Paige
Sanchit Misra
Stanislaw Jastrzebski
Bharat Kaul
Doina Precup
José Miguel Hernández-Lobato
Marwin Segler
Michael Bronstein
Anne Marinier
Mike Tyers
Yoshua Bengio
Despite substantial progress in machine learning for scientific discovery in recent years, truly de novo design of small molecules which exh… (voir plus)ibit a property of interest remains a significant challenge. We introduce LambdaZero, a generative active learning approach to search for synthesizable molecules. Powered by deep reinforcement learning, LambdaZero learns to search over the vast space of molecules to discover candidates with a desired property. We apply LambdaZero with molecular docking to design novel small molecules that inhibit the enzyme soluble Epoxide Hydrolase 2 (sEH), while enforcing constraints on synthesizability and drug-likeliness. LambdaZero provides an exponential speedup in terms of the number of calls to the expensive molecular docking oracle, and LambdaZero de novo designed molecules reach docking scores that would otherwise require the virtual screening of a hundred billion molecules. Importantly, LambdaZero discovers novel scaffolds of synthesizable, drug-like inhibitors for sEH. In in vitro experimental validation, a series of ligands from a generated quinazoline-based scaffold were synthesized, and the lead inhibitor N-(4,6-di(pyrrolidin-1-yl)quinazolin-2-yl)-N-methylbenzamide (UM0152893) displayed sub-micromolar enzyme inhibition of sEH.
2023-12-31
arXiv (prépublication)
doi.org
arxiv.org