In silico identification of bioisosteric functional groups.
Bioisosteric replacement is a standard technique that is used in medicinal chemistry to design analogs of bioactive molecules with similar activity and with additional improved characteristics. However, successful bioisosteric design requires significant prior chemical knowledge, and the identification of a replacement group with an optimal balance of steric, hydrophobic, electronic and hydrogen-bonding properties that all influence ligand-receptor interactions usually requires a demanding procedure of trial and error. In this article, various methods that can help medicinal chemists to identify bioisosteric analogs are reviewed, beginning with classical techniques using experimental group properties. Methods to find bioisosteric pairs based on the analysis of large molecular databases are discussed. Various descriptors to characterize properties of functional groups are described, and methods to identify bioisosteric replacement by conducting property similarity search are presented. Examples of tools that help chemists to navigate within the group functional property space are also provided.
Ertl
Peter
P
Novartis Institutes for BioMedical Research, Basel, Switzerland. peter.ertl@novartis.com
D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D048088:Informatics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D013678:Technology, Pharmaceutical / Q000379:methods*
D004364:Pharmaceutical Preparations; D011506:Proteins