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Anti-Proliferative Effect of Potential LSD1/CoREST Inhibitors Based on Molecular Dynamics Model for Treatment of
Hiba Zalloum1, Waleed Zalloum2, Tareq Hameduh1
1Hamdi Mango Research Center for Scientific Research, The University of Jordan, Amman 11942, Jordan.
Background:
Lysine-specific demethylase is a demethylase enzyme that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is associated with inferior prognosis. LSD1 is associated with its corepressor protein CoREST, and utilizes tetrahydrofolate as a cofactor to accept CH2 from the demethylation process. The fact that the cofactor is best bound to the active site inspired us to explore its interactions to LSD1/CoREST enzyme complex utilizing molecular dynamics simulation, which aids designing novel and potent inhibitors.
Objective:
In this study we minted to identify a new potential LSD1/CoREST inhibitors and test the potency and the safety of such inhibitors against human neuroblastoma and fibroblast cells lines.
Methods:
We have implemented a previously derived model from the molecular dynamics simulation study and the key contacts to the active site in a subsequent structure based drug design and in-silico screening, which revealed a number of potential inhibitors toward LSD1/CoREST complex. The anti-proliferative activities of the identified compounds will be tested against neuroblastoma SH-SY5Y cancer cell line which known to highly express LSD1/CoREST complex.
Results:
In-silico mining on National Cancer Institute (NCI) database identified 55 promising and structurally diverse inhibitors. Applying the abovementioned molecular modeling procedure yielded four compounds of LSD1/CoREST inhibiters with IC50 < 2µM. The four lead compounds were tested against SH-SY5Y neuroblastoma cell line that known to express high level of LSD1 and illustrated a potent activity with an IC50 ranging from 0.195 to 1.52µM. To estimate the toxicity of the selective leads, they were tested against normal fibroblast cells and scored a relatively high IC50 ranging from 0.303 to ≥ 100µM.
Conclusion:
Our model revealed promising inhibitors that can be used in treating cancers that overexpress the LSD1 enzyme such as the SH-SY5Y neuroblastoma.
Insights
Researchers identified potent LSD1/CoREST inhibitors for cancer treatment. These compounds show strong anti-proliferative activity against neuroblastoma cells with minimal toxicity to normal cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Lysine-specific demethylase 1 (LSD1) is a key enzyme in epigenetic regulation, implicated in various cancers by promoting proliferation and metastasis.
- LSD1 functions within a complex with CoREST, utilizing tetrahydrofolate as a cofactor.
- Understanding LSD1/CoREST interactions is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To identify novel inhibitors targeting the LSD1/CoREST enzyme complex.
- To evaluate the potency and safety of these inhibitors against human neuroblastoma and fibroblast cell lines.
Main Methods:
- Utilized molecular dynamics simulations to model LSD1/CoREST interactions.
- Employed structure-based drug design and in-silico screening of the National Cancer Institute (NCI) database.
- Tested anti-proliferative activity against SH-SY5Y neuroblastoma cells and normal fibroblast cells.
Main Results:
- Identified 55 diverse potential inhibitors through in-silico screening.
- Four lead compounds demonstrated potent LSD1/CoREST inhibition with IC50 < 2µM.
- Lead compounds showed significant anti-proliferative effects on neuroblastoma cells (IC50 0.195–1.52µM) and favorable safety profiles on fibroblasts (IC50 0.303–≥ 100µM).
Conclusions:
- The developed computational model successfully identified promising LSD1/CoREST inhibitors.
- These inhibitors represent potential therapeutic agents for cancers overexpressing LSD1, such as neuroblastoma.
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