title: Applying medicinal chemistry transformations and multiparameter optimization to guide the search for high-quality leads and candidates.
abstract: In this article we describe a computational method that automatically generates chemically relevant compound ideas from an initial molecule, closely integrated with in silico models, and a probabilistic scoring algorithm to highlight the compound ideas most likely to satisfy a user-defined profile of required properties. The new compound ideas are generated using medicinal chemistry 'transformation rules' taken from examples in the literature. We demonstrate that the set of 206 transformations employed is generally applicable, produces a wide range of new compounds, and is representative of the types of modifications previously made to move from lead-like to drug-like compounds. Furthermore, we show that more than 94% of the compounds generated by transformation of typical drug-like molecules are acceptable to experienced medicinal chemists. Finally, we illustrate an application of our approach to the lead that ultimately led to the discovery of duloxetine, a marketed serotonin reuptake inhibitor.
authors: Optibrium Ltd., 7226 Cambridge Research Park, Beach Drive, Cambridge, United Kingdom. matt.segall@optibrium.com
authors: Matthew
authors: M
authors: Segall
authors: Ed
authors: E
authors: Champness
authors: Chris
authors: C
authors: Leeding
authors: Ryan
authors: R
authors: Lilien
authors: Ramgopal
authors: R
authors: Mettu
authors: Brian
authors: B
authors: Stevens
mesh_terms: D000465:Algorithms; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D000068736:Duloxetine Hydrochloride; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D012107:Research Design; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000378:metabolism; D012984:Software; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism
chemical_list: D000068736:Duloxetine Hydrochloride; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes