Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2.
Jul 8, 2024·
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Eguida, M.
Bret, G.
Sindt, F.
Li, F.
Chau, I.
Ackloo, S.
Arrowsmith, C.
Bolotokova, A.
Ghiabi, P.
Gibson, E.
Halabelian, L.
Houliston, S.
Harding, R. J.
Hutchinson, A.
Loppnau, P.
Perveen, S.
Seitova, A.
Zeng, H.
Schapira, M.
Rognan, D.
Abstract
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.
Type
Publication
Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2., Journal of chemical information and modeling 2024 64 (13), 5344-5355