title: Using chiral molecules as an approach to address low-druggability recognition sites.
abstract: The content of chiral carbon atoms or structural complexity, which is known to correlate well with relevant physicochemical properties of small molecules, represents a promising descriptor that could fill the gap in existing drug discovery between ligand library filtering rules and the corresponding properties of the target's recognition site. Herein, we present an in silico study on the yet unclear underlying correlations between molecular complexity and other more sophisticated physicochemical and biological properties. By analyzing thousands of protein-ligand complexes from DrugBank, we show that increasing molecular complexity of drugs is an approach to addressing particularly low-druggability and polar recognition sites. We also show that biologically relevant protein classes characteristically bind molecules with a certain degree of structural complexity. Three distinct behaviors toward drug recognition are described. The reported results set the basis for a better understanding of protein-drug recognition, and open the possibility of including target information in the filtering of large ligand libraries for screening.
authors.affiliation: Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, University of Freiburg, 79104, Germany.
authors.forename: Xavier
authors.initials: X
authors.lastname: Lucas
authors.forename: Stefan
authors.initials: S
authors.lastname: Günther
mesh_terms: D001665:Binding Sites; D002244:Carbon / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D011506:Proteins; D054852:Small Molecule Libraries; D002244:Carbon
keywords: chirality; drug design; druggability; library preparation; molecular recognition; structural complexity