In silico screening of natural products as uPAR inhibitors via multiple structure-based docking and molecular
Song Xie1, Guiqian Yang1, Juhong Wu1
1College of Chemistry, Fuzhou University, Fuzhou, China.
Abstract:
Cancer remains one of the most pressing challenges to global healthcare, exerting a significant impact on patient life expectancy. Cancer metastasis is a critical determinant of the lethality and treatment resistance of cancer. The urokinase-type plasminogen activator receptor (uPAR) shows great potential as a target for anticancer and antimetastatic therapies. In this work, we aimed to identify potential uPAR inhibitors by structural dynamics-based virtual screenings against a natural product library on four representative apo-uPAR structural models recently derived from long-timescale molecular dynamics (MD) simulations. Fifteen potential inhibitors (NP1-NP15) were initially identified through molecular docking, consensus scoring, and visual inspection. Subsequently, we employed MD-based molecular mechanics-generalized Born surface area (MM-GBSA) calculations to evaluate their binding affinities to uPAR. Structural dynamics analyses further indicated that all of the top 6 compounds exhibited stable binding to uPAR and interacted with the critical residues in the binding interface between uPAR and its endogenous ligand uPA, suggesting their potential as uPAR inhibitors by interrupting the uPAR-uPA interaction. We finally predicted the ADMET properties of these compounds. The natural products NP5, NP12, and NP14 with better binding affinities to uPAR than the uPAR inhibitors previously discovered by us were proven to be potentially orally active in humans. This work offers potential uPAR inhibitors that may contribute to the development of novel effective anticancer and antimetastatic therapeutics.
Insights
Researchers identified novel natural product inhibitors targeting urokinase-type plasminogen activator receptor (uPAR) to combat cancer metastasis. Compounds NP5, NP12, and NP14 show promise as orally active anticancer therapeutics by blocking uPAR-uPA interactions.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Cancer metastasis is a major cause of cancer-related deaths and treatment resistance.
- Urokinase-type plasminogen activator receptor (uPAR) is a key target for anticancer and antimetastatic therapies.
Purpose of the Study:
- To identify novel natural product inhibitors of uPAR using structure-based virtual screening.
- To evaluate the binding affinity and dynamics of potential inhibitors against uPAR.
Main Methods:
- Long-timescale molecular dynamics (MD) simulations to generate apo-uPAR models.
- Molecular docking, consensus scoring, and visual inspection for initial inhibitor identification.
- MD-based MM-GBSA calculations and structural dynamics analyses for binding affinity and stability assessment.
- ADMET property prediction for top-ranked compounds.
Main Results:
- Fifteen potential uPAR inhibitors (NP1-NP15) were identified from a natural product library.
- Top 6 compounds demonstrated stable binding to uPAR, interacting with critical residues of the uPAR-uPA interface.
- Natural products NP5, NP12, and NP14 exhibited superior binding affinity compared to previously discovered inhibitors.
- NP5, NP12, and NP14 were predicted to have favorable oral bioavailability.
Conclusions:
- This study identified promising natural product-derived uPAR inhibitors.
- NP5, NP12, and NP14 represent potential candidates for developing novel anticancer and antimetastatic therapeutics.
- The identified compounds may offer effective strategies for interrupting uPAR-mediated cancer progression.
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