Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2.
J Chem Inf Model
; 64(13): 5344-5355, 2024 Jul 08.
Article
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| MEDLINE
| ID: mdl-38916159
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Simulación del Acoplamiento Molecular
/
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina
Idioma:
En
Revista:
J Chem Inf Model
Asunto de la revista:
INFORMATICA MEDICA
/
QUIMICA
Año:
2024
Tipo del documento:
Article