title: Charting the chemical space of target sites: insights into the binding modes of amine and amidine groups.
abstract: Nowadays there is growing awareness that the translation of the increasing number of lead compounds into clinical candidates is still a slow and often inefficient process. In order to facilitate the lead optimization procedure, due consideration must be given to the use of the right bioisosteric replacements. Very recently, we reported that exploring a chemical space of binding sites is a more effective strategy for studying the bioisosteric relationships existing among functional groups. As a continuation of our work in this field, we report herein the construction of a chemical space covered by binding sites of small molecules containing diverse amine and amidine groups. The analysis of the differences in some properties of the binding sites of these functional groups allow for gaining insights into the binding modes of positively charged groups. In addition, this study pinpoints that different types of interactions and bioisosteric relationships exist among primary, secondary, tertiary, quaternary amine, and amidine moieties.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Universita di Perugia, via del Liceo 1, 06127 Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Roberto
authors.initials: R
authors.lastname: Nuti
authors.forename: Gokcen
authors.initials: G
authors.lastname: Eren
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006860:Hydrogen Bonding; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D008670:Metals / Q000737:chemistry; D008958:Models, Molecular; D065108:Ornithine Decarboxylase Inhibitors; D010100:Oxygen / Q000737:chemistry; D025341:Principal Component Analysis; D011487:Protein Conformation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry; D014867:Water / Q000737:chemistry; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000578:Amidines; D000588:Amines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D008670:Metals; D065108:Ornithine Decarboxylase Inhibitors; D010100:Oxygen; D017027:Protein Tyrosine Phosphatases; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014867:Water; D000099150:Receptor, Farnesoid X-Activated