Related Experiment Video
Updated: Aug 18, 2025
Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
Published on: December 21, 2019
Discovery of Mcl-1 inhibitors through virtual screening, molecular dynamics simulations and in vitro experiments
Jianda Yue1, Yaqi Li1, Fengjiao Li1
1The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
Abstract:
As a member of the B-cell lymphoma 2 (Bcl-2) protein family, the myeloid leukemia cell differentiation protein (Mcl-1) can inhibit apoptosis and plays an active role in the process of tumor escape from apoptosis. Therefore, inhibition of Mcl-1 protein can effectively promote the apoptosis of tumor cells and may also reduce tumor cell resistance to drugs targeting other anti-apoptotic proteins. This research is dedicated to the development of Mcl-1 inhibitors, aiming to provide more references for lead compounds with different scaffolds for the development of targeted anticancer drugs. We obtained a series of small molecules with a common core skeleton through molecular docking from Specs database and searched the core structure in ZINC database for more similar small molecules. Collecting these small molecules for preliminary experimental screening, we found a batch of active compounds, and selected two small molecules with the strongest inhibitory activity on B16F10 cells: compound 7 and compound 1. Their IC50s are 7.86 ± 1.25 and 24.72 ± 1.94 μM, respectively. These two compounds were also put into cell scratch test for B16F10 cells and cell viability assay of other cell lines. Furthermore, through molecular dynamics (MD) simulation analysis, we found that compound 7 formed strong binding with the key P2, P3 pocket and ARG 263 of Mcl-1. Finally, ADME results showed that compound 7 performs well in terms of drug similarity. In conclusion, this study provides hits with co-scaffolds that may aid in the design of effective clinical drugs targeting Mcl-1 and the future drug development.
Insights
Researchers developed novel Mcl-1 inhibitors to combat cancer. Compound 7 showed strong activity against B16F10 cells, demonstrating potential for targeted anticancer drug development.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Myeloid leukemia cell differentiation protein (Mcl-1) is a member of the B-cell lymphoma 2 (Bcl-2) protein family that inhibits apoptosis.
- Mcl-1 plays a critical role in tumor cells evading apoptosis and can contribute to drug resistance.
- Targeting Mcl-1 offers a promising strategy to enhance cancer cell apoptosis and overcome therapeutic resistance.
Purpose of the Study:
- To discover and develop novel small molecule inhibitors targeting Mcl-1.
- To identify lead compounds with diverse scaffolds for anticancer drug development.
- To provide new references for the design of Mcl-1-targeted therapies.
Main Methods:
- Molecular docking was used to identify small molecules with a common core skeleton from the Specs database.
- The ZINC database was searched for similar molecules based on the identified core structure.
- Preliminary experimental screening, cell-based assays (IC50, cell scratch, viability), molecular dynamics simulations, and ADME analysis were performed.
Main Results:
- Two potent Mcl-1 inhibitors, compound 7 and compound 1, were identified with IC50 values of 7.86 ± 1.25 μM and 24.72 ± 1.94 μM against B16F10 cells, respectively.
- Compound 7 demonstrated strong binding interactions with key pockets (P2, P3) and residue ARG 263 of Mcl-1, as revealed by molecular dynamics simulations.
- Compound 7 exhibited favorable drug-like properties based on ADME predictions.
Conclusions:
- The identified compounds, particularly compound 7, represent promising hits with co-scaffolds for Mcl-1-targeted anticancer drug development.
- This research provides valuable insights and potential lead compounds for future clinical drug design against Mcl-1.
- The study highlights the therapeutic potential of inhibiting Mcl-1 to promote cancer cell apoptosis and overcome drug resistance.
