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Hunting potential SIRT2 inhibitors towards cancer treatment: Drug repurposing, molecular dynamics, and binding energy
Mahmoud A A Ibrahim1, Khlood A A Abdeljawaad2, Alaa H M Abdelrahman3
1Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt; Department of Engineering, College of Engineering and Technology, University of Technology and Applied Sciences, Nizwa, 611, Oman; School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4000, South Africa.
Abstract:
The histone deacetylase group of proteins, which includes the sirtuins, contributes to several cellular processes and is intimately involved in cancer development. Sirtuins type two (SIRT2) is a constituent of the human sirtuin family, which modulates a range of biological functions and is recognized as a potential biomarker for numerous cancers. The impact of SIRT2 knockout on tumorigenesis is debated and varies with the type of tumor; nonetheless, pharmacological inhibition of SIRT2 results exclusively in growth inhibition of diverse cancer cell lines. As a result, SIRT2 regulation is thought to be a viable protein for treating cancer. Herein, the DrugBank database, containing >14,000 drug molecules, was repurposed to find potential anticancer medications that have the capacity to inhibit the SIRT2 protein utilizing in-silico techniques. In light of the experimental findings, the capability of AutoDock Vina1.1.2 software to anticipate the docking scores and poses of the SIRT2 inhibitors was assessed. SirReal2, a potential SIRT2 inhibitor, was the controller for this study. Notably, drugs with docking scores less than SiReal2 were chosen and introduced to molecular dynamics (MD) simulations, accompanied by binding affinities estimations utilizing the MM-GBSA approach. Interestingly, MM-GBSA calculations demonstrated that five drugs, namely DB11526, DB11977, DB15133, DB04739, and DB04632, revealed potential affinities as SIRT2 inhibitors exhibiting ΔGbinding less than -50.0 kcal/mol. The post-MD analyses were inspected for DB11526, DB11977, DB15133, DB04739, and DB04632, indicating excellent steadiness of these drugs bound to SIRT2 protein throughout the 200 ns MD. The ADMET features were also examined and were acceptable. These findings suggested that more attention should be paid to DB11526, DB11977, DB15133, DB04739, and DB04632 as SIRT2 inhibitors utilizing in-vitro/in-vivo assays to treat cancer disease.
Insights
This study repurposed existing drugs to find new SIRT2 inhibitors for cancer treatment. Five drug candidates, including DB11526, showed strong potential for inhibiting SIRT2 and warrant further investigation in cancer therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- Histone deacetylases, including sirtuins, play a role in cellular processes and cancer development.
- Sirtuin 2 (SIRT2) is a potential cancer biomarker, and its inhibition shows promise for cancer treatment.
- Pharmacological inhibition of SIRT2 leads to growth inhibition in various cancer cell lines.
Purpose of the Study:
- To identify potential SIRT2 inhibitors from the DrugBank database using in-silico methods.
- To evaluate the efficacy of identified compounds as potential anticancer drugs targeting SIRT2.
- To assess the drug-likeness and stability of potential SIRT2 inhibitors.
Main Methods:
- In-silico drug repurposing using AutoDock Vina for docking simulations.
- Molecular Dynamics (MD) simulations to assess the stability of drug-protein complexes.
- MM-GBSA calculations for binding affinity estimation.
- ADMET property analysis for drug-likeness.
Main Results:
- Five drug candidates (DB11526, DB11977, DB15133, DB04739, DB04632) exhibited significant binding affinities to SIRT2 (ΔGbinding < -50.0 kcal/mol).
- MD simulations confirmed the stability of these five drug candidates bound to SIRT2 over 200 ns.
- The identified compounds demonstrated acceptable ADMET properties.
Conclusions:
- DB11526, DB11977, DB15133, DB04739, and DB04632 are promising SIRT2 inhibitors with potential for cancer therapy.
- Further in-vitro and in-vivo studies are recommended to validate these findings.
- In-silico drug repurposing is an effective strategy for identifying novel anticancer agents targeting SIRT2.
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