title: SYNOPSIS: SYNthesize and OPtimize System in Silico.
abstract: We present a de novo design program called SYNOPSIS, that includes a synthesis route for each generated molecule. SYNOPSIS designs novel molecules by starting from a database of available molecules and simulating organic synthesis steps. This way of generating molecules imposes synthetic accessibility on the molecules. In addition to a starting database, a fitness function is needed that calculates the value of a desired property for an arbitrary molecule. The values obtained from this function guide the design process in optimizing the molecules toward an optimal value of the calculated property. Two applications are described. The first uses an electric dipole moment calculation to generate molecules possessing a strong dipole moment. The second makes use of the three-dimensional structure of a viral enzyme in order to generate high affinity ligands. Twenty eight compounds designed with the program resulted in 18 synthesized and tested compounds, 10 of which showed HIV inhibitory activity in vitro.
authors.affiliation: Center for Molecular Design, Janssen Pharmaceutica N.V., Antwerpsesteenweg 37, B-2350 Vosselaar, Belgium. mvinkers@janbe.jnj.com
authors.forename: H Maarten
authors.initials: HM
authors.lastname: Vinkers
authors.forename: Marc R
authors.initials: MR
authors.lastname: de Jonge
authors.forename: Frederik F D
authors.initials: FF
authors.lastname: Daeyaert
authors.forename: Jan
authors.initials: J
authors.lastname: Heeres
authors.forename: Lucien M H
authors.initials: LM
authors.lastname: Koymans
authors.forename: Joop H
authors.initials: JH
authors.lastname: van Lenthe
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lewi
authors.forename: Henk
authors.initials: H
authors.lastname: Timmerman
authors.forename: Koen
authors.initials: K
authors.lastname: Van Aken
authors.forename: Paul A J
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D015195:Drug Design; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D012984:Software
chemical_list: D019380:Anti-HIV Agents; D004364:Pharmaceutical Preparations; D018894:Reverse Transcriptase Inhibitors