The concept of template-based de novo design from drug-derived molecular fragments and its application to TAR RNA.
Principles of fragment-based molecular design are presented and discussed in the context of de novo drug design. The underlying idea is to dissect known drug molecules in fragments by straightforward pseudo-retro-synthesis. The resulting building blocks are then used for automated assembly of new molecules. A particular question has been whether this approach is actually able to perform scaffold-hopping. A prospective case study illustrates the usefulness of fragment-based de novo design for finding new scaffolds. We were able to identify a novel ligand disrupting the interaction between the Tat peptide and TAR RNA, which is part of the human immunodeficiency virus (HIV-1) mRNA. Using a single template structure (acetylpromazine) as reference molecule and a topological pharmacophore descriptor (CATS), new chemotypes were automatically generated by our de novo design software Flux. Flux features an evolutionary algorithm for fragment-based compound assembly and optimization. Pharmacophore superimposition and docking into the target RNA suggest perfect matching between the template molecule and the designed compound. Chemical synthesis was straightforward, and bioactivity of the designed molecule was confirmed in a FRET assay. This study demonstrates the practicability of de novo design to generating RNA ligands containing novel molecular scaffolds.
Schüller
Andreas
A
Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 7, Chair for Chem- and Bioinformatics Siesmayerstr. 70, 60323 Frankfurt am Main, Germany.
Suhartono
Marcel
M
Fechner
Uli
U
Tanrikulu
Yusuf
Y
Breitung
Sven
S
Scheffer
Ute
U
Göbel
Michael W
MW
Schneider
Gisbert
G
D015195:Drug Design; D005453:Fluorescence; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013698:Templates, Genetic
D012367:RNA, Viral