Core Hopping

Comprehensive ligand- and receptor-based scaffold exploration for lead optimization

The Advantages of Core Hopping

Compounds can fail in drug development, or worse, commercially-available medications can be recalled due to unforeseen toxicity, selectivity, potency, and other unsuitable physicochemical properties. These issues can often be a function of undesirable core properties. Core hopping allows for the rapid screening of novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties while preserving key R-group interactions. In addition to lead optimization, core hopping can also be valuable in idea generation for novel derivatives to a known drug.

Schrödinger's Core Hopping program not only provides the traditional ligand-based methods for exploring different scaffolds, but also offers a receptor-based method that will accurately account for detailed ligand-receptor interactions of compounds containing novel cores.

Attachment-based core hopping:
This ligand-based method aligns the starting compound’s R-group attachments with sets of attachment bonds in candidate cores. The threaded algorithm takes full advantage of modern, multi-core computing technology to provide the highest throughput.

Shape-based core hopping:
This ligand-based method uses Schrödinger’s Phase Shape technology to ensure that the shape and chemical nature of the candidate scaffolds are sufficiently similar to those of the starting compound, while simultaneously achieving good joining geometry for R-group placement. Phase Shape's efficient algorithm makes this core hopping approach a perfect balance between speed and accuracy.

Receptor-based core hopping:
The unique receptor-based core hopping method takes advantage of Schrödinger's Glide docking analysis. Scaffold replacements are carried out in the active site, guided by a known binding pose where candidate cores are rewarded for favorable interactions with the receptor and penalized for the reverse. Users may optionally specify core-receptor interactions, such as hydrogen bonds, that a candidate scaffold must form with the receptor. This method returns novel compounds with ligand-receptor interactions that are most faithful to those of the starting compound.

Automatic linker addition:
The attachment- and receptor-based core hopping methods provide the option to automatically insert linkers to a candidate core's periphery to achieve proper R-group connectivity for any replacement scaffolds that exhibit desired properties, but are too small to align with the attachment bonds of the starting compound.

Core libraries:
Schrödinger provides a downloadable bundle of curated scaffold libraries for molecular design. Users can easily add their own scaffold structures to these libraries, or use them as is. The scaffold libraries in the bundle are regularly updated by in-house scientists at Schrödinger.

Intuitive graphical user interface:
Schrödinger’s intuitive graphical user interface, Maestro, provides step-by-step panels for straightforward set-up of experiments, easy visualization and efficient analysis of Core Hopping results.

Citations and Acknowledgements

Schrödinger Release 2023-4: Core Hopping, Schrödinger, LLC, New York, NY, 2023.

· "Acylguanidine Beta Secretase 1 Inhibitors: A Combined Experimental and Free Energy Perturbation Study"

Keränen, H.; Pérez-Benit, L.; Ciordia, M.; Delgado, F.; Steinbrecher, T.B.; Oehlrich, D.; van Vlijmen, H.; Trabanco, A.A.; Tresadern, G., J. Chem. Theory Comput., 2017, 13, 1439-1453

"Design Potential Selective Inhibitors for Treating Cancer by Targeting the Src Homology 2 (SH2) Domain-Containing Phosphatase 2 (Shp2) with Core Hopping Approach"

Duan Y.Q.; Ma Y.; Wang X.J.; Jin Y.Y.; Wang R.L.; Dong W.L.; Xu W.R.; Kong D.X.; Wang S.Q., Protein Pept. Lett., 2014, (21)6, 556-563(8)

"Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors"

Zhang L.S.; Wang S.Q.; Xu W.R.; Wang R.L.; Wang J.F., PLos ONE, 2012, 7(10), DOI: 10.1371/journal.pone.0048453