Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2.

Autor: Eguida M; Laboratoire d'innovation thérapeutique, UMR7200 CNRS-Université de Strasbourg, F-67400 Illkirch, Strasbourg, France., Bret G; Laboratoire d'innovation thérapeutique, UMR7200 CNRS-Université de Strasbourg, F-67400 Illkirch, Strasbourg, France., Sindt F; Laboratoire d'innovation thérapeutique, UMR7200 CNRS-Université de Strasbourg, F-67400 Illkirch, Strasbourg, France., Li F; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Chau I; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Ackloo S; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Arrowsmith C; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada., Bolotokova A; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Ghiabi P; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Gibson E; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Halabelian L; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada., Houliston S; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada., Harding RJ; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5G 1L7, Canada., Hutchinson A; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Loppnau P; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Perveen S; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Seitova A; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Zeng H; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Schapira M; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5G 1L7, Canada., Rognan D; Laboratoire d'innovation thérapeutique, UMR7200 CNRS-Université de Strasbourg, F-67400 Illkirch, Strasbourg, France.
Jazyk: angličtina
Zdroj: Journal of chemical information and modeling [J Chem Inf Model] 2024 Jul 08; Vol. 64 (13), pp. 5344-5355. Date of Electronic Publication: 2024 Jun 25.
DOI: 10.1021/acs.jcim.4c00601
Abstrakt: We herewith applied a priori a generic hit identification method (POEM) for difficult targets of known three-dimensional structure, relying on the simple knowledge of physicochemical and topological properties of a user-selected cavity. Searching for local similarity to a set of fragment-bound protein microenvironments of known structure, a point cloud registration algorithm is first applied to align known subpockets to the target cavity. The resulting alignment then permits us to directly pose the corresponding seed fragments in a target cavity space not typically amenable to classical docking approaches. Last, linking potentially connectable atoms by a deep generative linker enables full ligand enumeration. When applied to the WD40 repeat (WDR) central cavity of leucine-rich repeat kinase 2 (LRRK2), an unprecedented binding site, POEM was able to quickly propose 94 potential hits, five of which were subsequently confirmed to bind in vitro to LRRK2-WDR.
Databáze: MEDLINE
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