{Reference Type}: Journal Article
{Title}: Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2.
{Author}: 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 RJ;Hutchinson A;Loppnau P;Perveen S;Seitova A;Zeng H;Schapira M;Rognan D;
{Journal}: J Chem Inf Model
{Volume}: 64
{Issue}: 13
{Year}: 2024 Jul 8
{Factor}: 6.162
{DOI}: 10.1021/acs.jcim.4c00601
{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.