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Article

Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors

1
Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Kurt-Mothes-Str.3, 06120 Halle/Saale, Germany
2
Institute for Organic Chemistry, University of Freiburg, Albertstr. 21, 79104 Freiburg, Germany
3
Institute of Pharmaceutical Sciences, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany
4
Department of Urology and Center for Clinical Research, University Freiburg Medical Center, Breisacherstr. 66, 79106 Freiburg, Germany
5
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
6
CIBSS—Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Giulio Poli
Int. J. Mol. Sci. 2021, 22(11), 5910; https://doi.org/10.3390/ijms22115910
Received: 5 May 2021 / Revised: 24 May 2021 / Accepted: 26 May 2021 / Published: 31 May 2021
(This article belongs to the Special Issue Computational Methods in Drug Design)
The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings. View Full-Text
Keywords: Spindlin1; structure–activity relationship (SAR); docking; molecular dynamics (MD) simulations; MM-GBSA Spindlin1; structure–activity relationship (SAR); docking; molecular dynamics (MD) simulations; MM-GBSA
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MDPI and ACS Style

Luise, C.; Robaa, D.; Regenass, P.; Maurer, D.; Ostrovskyi, D.; Seifert, L.; Bacher, J.; Burgahn, T.; Wagner, T.; Seitz, J.; Greschik, H.; Park, K.-S.; Xiong, Y.; Jin, J.; Schüle, R.; Breit, B.; Jung, M.; Sippl, W. Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors. Int. J. Mol. Sci. 2021, 22, 5910. https://doi.org/10.3390/ijms22115910

AMA Style

Luise C, Robaa D, Regenass P, Maurer D, Ostrovskyi D, Seifert L, Bacher J, Burgahn T, Wagner T, Seitz J, Greschik H, Park K-S, Xiong Y, Jin J, Schüle R, Breit B, Jung M, Sippl W. Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors. International Journal of Molecular Sciences. 2021; 22(11):5910. https://doi.org/10.3390/ijms22115910

Chicago/Turabian Style

Luise, Chiara, Dina Robaa, Pierre Regenass, David Maurer, Dmytro Ostrovskyi, Ludwig Seifert, Johannes Bacher, Teresa Burgahn, Tobias Wagner, Johannes Seitz, Holger Greschik, Kwang-Su Park, Yan Xiong, Jian Jin, Roland Schüle, Bernhard Breit, Manfred Jung, and Wolfgang Sippl. 2021. "Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors" International Journal of Molecular Sciences 22, no. 11: 5910. https://doi.org/10.3390/ijms22115910

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