Scaffold hopping via ANCHOR.QUERY: β-lactams as potent p53-MDM2 antagonists†

S Shaabani; C G Neochoritis; A Twarda-Clapa; B Musielak; T A Holak; A Dömling

doi:10.1039/C7MD00058H

Scaffold hopping via ANCHOR.QUERY: β-lactams as potent p53-MDM2 antagonists^†

Medchemcomm. 2017 May 1;8(5):1046-1052. doi: 10.1039/C7MD00058H. Epub 2017 Mar 15.

Authors

S Shaabani^{1

2}, C G Neochoritis¹, A Twarda-Clapa^{3

4}, B Musielak⁵, T A Holak^{3

5}, A Dömling¹

Affiliations

¹ Department of Drug Design, University of Groningen, The Netherlands.
² Faculty of Chemistry, Shahid Beheshti University, Tehran, Iran.
³ Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
⁴ Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
⁵ Department of Chemistry, Jagiellonian University, Krakow, Poland.

Abstract

Using the pharmacophore-based virtual screening platform ANCHOR.QUERY, we morphed our recently described Ugi-4CR scaffold towards a β-lactam scaffold with potent p53-MDM2 antagonizing activities. 2D-HSQC and FP measurements confirm potent MDM2 binding. Molecular modeling studies are used to understand the observed SAR in the β-lactam series.

Grants and funding

R01 GM097082/GM/NIGMS NIH HHS/United States