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Published on: December 1, 2020
In silico identification of 20S proteasome-β5 subunit inhibitors using structure-based virtual screening
Ouadie Mohamed El Yaagoubi1, Wahiba Ezzemani2,3, Larbi Oularbi4,5
1Laboratory of Biochemistry, Environment and Agri-Food (URAC 36), Faculty of Sciences and Techniques-Mohammedia, Hassan II University of Casablanca, Morocco.
Abstract:
Proteasome inhibitors have effective anti-tumor activity in cell culture and can induce apoptosis by interfering with the degradation of cell cycle proteins. 20S Proteasome is acknowledged to be a satisfactory target that has persistent properties against the human immune defense and is obligatory for the degradation of some vital proteins. This study aimed to identify potential inhibitors against 20S proteasome, specifically the β5 subunit, using structure-based virtual screening and molecular docking to reduce the number of ligands that should be eligible for experimental assays. A total of 4961 molecules with anticancer activity were screened from the ASINEX database. The filtered compounds that showed higher docking affinity were then used in more sophisticated molecular docking simulations with AutoDock Vina for validation. Finally, six drug molecules (BDE 28974746, BDE 25657353, BDE 29746159, BDD 27844484, BDE 29746109, and BDE 29746162) exhibited highly significant interactions compared to the positive controls were retained. Among these six molecules, three molecules (BDE 28974746, BDE 25657353, and BDD 27844484) showed high binding affinity and binding energy compared with Carfilzomib and Bortezomib. Molecular simulation and dynamics studies of the top three drug molecules in each case allowed us to draw further conclusions about their stability with the β5 subunit. Computed absorption, distribution, metabolism, excretion and toxicity studies on these derivatives showed encouraging results with very low toxicity, distribution, and absorption. These compounds may serve as potential hits for further biological evaluation in the development of new proteasome inhibitors.Communicated by Ramaswamy H. Sarma.
Insights
Researchers identified novel 20S proteasome inhibitors targeting the β5 subunit. Three promising drug candidates show high binding affinity and low toxicity, advancing proteasome inhibitor drug development.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Proteasome inhibitors demonstrate anti-tumor activity by disrupting cell cycle protein degradation and inducing apoptosis.
- The 20S proteasome is a validated therapeutic target due to its essential role in protein degradation and relative resistance to immune responses.
- Targeting the 20S proteasome, particularly the β5 subunit, is crucial for developing effective cancer therapies.
Purpose of the Study:
- To identify novel inhibitors of the 20S proteasome, focusing on the β5 subunit.
- To utilize structure-based virtual screening and molecular docking to predict potential drug candidates.
- To reduce the number of compounds requiring experimental validation for proteasome inhibition.
Main Methods:
- Screened 4961 anticancer molecules from the ASINEX database using structure-based virtual screening.
- Employed molecular docking simulations, including AutoDock Vina, to assess binding affinity and validate initial screening results.
- Conducted molecular dynamics simulations and computed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies on top-ranked compounds.
Main Results:
- Identified six drug molecules with significant interactions against the 20S proteasome β5 subunit.
- Three compounds (BDE 28974746, BDE 25657353, BDD 27844484) exhibited high binding affinity and energy, comparable to positive controls Carfilzomib and Bortezomib.
- Top candidates demonstrated stability with the β5 subunit and favorable ADMET profiles, indicating low toxicity and good pharmacokinetic properties.
Conclusions:
- The identified drug molecules represent promising leads for developing new proteasome inhibitors.
- These compounds warrant further biological evaluation for their therapeutic potential in cancer treatment.
- Computational approaches effectively identified potent and safe drug candidates for the 20S proteasome β5 subunit.
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