Amino-carboxamide benzothiazoles as potential LSD1 hit inhibitors. Part I: Computational fragment-based drug design
Soraya Alnabulsi1, Enas A Al-Hurani1, Nizar A Al-Shar'i1
1Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
Abstract:
The lysine specific demethylase enzyme LSD1 regulates the function of histone proteins in cells through the demethylation of specific lysine amino acid residues. Being overexpressed in various cancers, LSD1 is considered as a validated target for cancer treatment. In this study, we describe the discovery of novel LSD1 inhibitors using computational fragment-based drug design approach. Structure-based screening of the Maybridge Ro3 2000 Diversity Fragment Library had identified two sets of fragments that bind to two different regions within the LSD1 active site. De Novo and Multiple Copy Simultaneous search (MCSS) docking, ligand efficiency (LE), and binding energy calculations (BE) had assisted the selection of the best scoring fragments that were grown to produce lead-like compounds. The final grown compounds were docked into the active site of the enzyme using flexible docking and their total binding energies were calculated in order to aid the selection of potential LSD1 inhibitors that will be synthesized and biologically evaluated. Six compounds were synthesized and biologically tested, of which two had showed a promising activity against LSD1. Compound 37, with an amino-carboxamide benzothiazole scaffold, showed the best inhibitory activity with an IC50 value of 18.4 μM. Compound 37 was chosen as an LSD1 hit inhibitor worthy of further optimization.
Insights
Researchers discovered new cancer drug candidates targeting the LSD1 enzyme using computational methods. Two compounds showed promising activity, with one (Compound 37) identified as a potential hit inhibitor for further development.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Computational Drug Design
Background:
- Lysine specific demethylase 1 (LSD1) is overexpressed in various cancers and is a validated therapeutic target.
- LSD1 regulates histone proteins by demethylating specific lysine residues, impacting gene expression and cellular function.
Purpose of the Study:
- To discover novel inhibitors of LSD1 using a computational fragment-based drug design approach.
- To identify lead-like compounds with potential for synthesis and biological evaluation against LSD1.
Main Methods:
- Structure-based screening of the Maybridge Ro3 2000 Diversity Fragment Library.
- De Novo and Multiple Copy Simultaneous Search (MCSS) docking, ligand efficiency (LE), and binding energy (BE) calculations.
- Flexible docking and binding energy calculations for grown compounds to select potential inhibitors.
Main Results:
- Two distinct fragment sets binding to different regions of the LSD1 active site were identified.
- Six compounds were synthesized and tested; two exhibited promising activity against LSD1.
- Compound 37, a benzothiazole derivative, demonstrated the best inhibitory activity with an IC50 of 18.4 μM.
Conclusions:
- Compound 37 is a promising LSD1 hit inhibitor identified through computational fragment-based drug design.
- Further optimization of Compound 37 is warranted for potential cancer therapeutic development.
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