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The concept of template-based de novo design from drug-derived molecular fragments and its application to TAR RNA

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Abstract

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.

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Acknowledgements

The authors would like to thank Steffi Becker for technical assistance. M.S. is grateful for a predoctoral fellowship from the Dr. Hilmer Foundation. This work was supported by the Beilstein-Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, and the Deutsche Forschungsgemeinschaft (SFB 579 “RNA-Ligand Interactions”, projects A3 and A11).

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Correspondence to Gisbert Schneider.

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Andreas Schüller and Marcel Suhartono contributed equally to this work.

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Schüller, A., Suhartono, M., Fechner, U. et al. The concept of template-based de novo design from drug-derived molecular fragments and its application to TAR RNA. J Comput Aided Mol Des 22, 59–68 (2008). https://doi.org/10.1007/s10822-007-9157-4

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  • DOI: https://doi.org/10.1007/s10822-007-9157-4

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