SYNOPSIS: SYNthesize and OPtimize System in Silico.
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.
Vinkers
H Maarten
HM
Center for Molecular Design, Janssen Pharmaceutica N.V., Antwerpsesteenweg 37, B-2350 Vosselaar, Belgium. mvinkers@janbe.jnj.com
de Jonge
Marc R
MR
Daeyaert
Frederik F D
FF
Heeres
Jan
J
Koymans
Lucien M H
LM
van Lenthe
Joop H
JH
Lewi
Paul J
PJ
Timmerman
Henk
H
Van Aken
Koen
K
Janssen
Paul A J
PA
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
D019380:Anti-HIV Agents; D004364:Pharmaceutical Preparations; D018894:Reverse Transcriptase Inhibitors