title: Comparison and druggability prediction of protein-ligand binding sites from pharmacophore-annotated cavity shapes.
abstract: Estimating the pairwise similarity of protein-ligand binding sites is a fast and efficient way of predicting cross-reactivity and putative side effects of drug candidates. Among the many tools available, three-dimensional (3D) alignment-dependent methods are usually slow and based on simplified representations of binding site atoms or surfaces. On the other hand, fast and efficient alignment-free methods have recently been described but suffer from a lack of interpretability. We herewith present a novel binding site description (VolSite), coupled to an alignment and comparison tool (Shaper) combining the speed of alignment-free methods with the interpretability of alignment-dependent approaches. It is based on the comparison of negative images of binding cavities encoding both shape and pharmacophoric properties at regularly spaced grid points. Shaper approximates the resulting molecular shape with a smooth Gaussian function and aligns protein binding sites by optimizing their volume overlap. Volsite and Shaper were successfully applied to compare protein-ligand binding sites and to predict their structural druggability.
authors: Laboratory of Therapeutic Innovation, UMR 7200 Université de Strasbourg/CNRS, Medalis Drug Discovery Center, F-67400 Illkirch, France.
authors: Jérémy
authors: J
authors: Desaphy
authors: Karima
authors: K
authors: Azdimousa
authors: Esther
authors: E
authors: Kellenberger
authors: Didier
authors: D
authors: Rognan
mesh_terms: D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins