Lone pair directionality in de novo drug design

Aniko T. Vigh

SPROUT is a de novo molecular structure design software suite developed over many years at the University of Leeds. The system provides a set of modules offering automatic methods for solving numerous problems associated with the structure based rational drug design process.

In de novo drug design, structures are generated to fit a set of steric and functional constraints. The constraints are usually derived by characterizing the binding sites – or target sites in SPROUT terminology – in order to find a ligand with good binding properties. Hydrogen bonds are important in receptor-ligand interactions and have always played an important part in the SPROUT process. Until recently, constraints for hydrogen bonds in SPROUT have controlled the H-bond length and the H-bond angle, but have not taken into account directionality of lone pairs, and as a result some ligands were generated which displayed poor geometry at acceptor atoms in that the acceptor lone pairs pointed away from the hydrogen. In order to prevent such bad interactions, additional constraints have been introduced for hydrogen bonds, with special regard to the lone pair geometry of acceptor atoms. Results (which will be presented) show that using lone pair directionality constraints in structure generation greatly improves the quality of structures generated, not only by excluding poor structures, but also by causing the generation of structures which would not have been found using the old H-bond constraints. The poster will include a detailed account of the constraints used for different hybridization patterns (sp2 etc) of lone pair bearing atoms.

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