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Artificial Intelligence Uncovers Natural MMP Inhibitor Crocin as a Potential Treatment of Thoracic Aortic Aneurysm
Feiran Qi1,2,3,4, Yan Liu1,2,3,4, Kunlin Zhang5,6,7
1Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Insights
Researchers identified crocin as a potential drug for thoracic aortic aneurysm and dissection (TAAD). This natural compound effectively inhibits matrix metalloproteinases (MMPs), crucial in TAAD development, showing therapeutic promise.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Bioinformatics
Background:
- Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular disease lacking effective drug treatments.
- Extracellular matrix organization is a key pathway in TAAD pathogenesis, with matrix metalloproteinases (MMPs) like MMP2 and MMP9 being significant targets.
- There is an urgent need for novel pharmaceutical therapies to target TAAD's underlying mechanisms.
Purpose of the Study:
- To identify novel natural compounds with therapeutic potential for TAAD by targeting MMPs.
- To investigate the efficacy of identified compounds in preclinical models of TAAD.
- To elucidate the mechanism of action of promising compounds, including their binding interactions with MMPs.
Main Methods:
- Bioinformatics analysis identified "extracellular matrix organization" as a critical pathway in TAAD.
- Virtual screening using Surflex-Dock identified nine natural compounds from the PubChem database.
- In vitro MMP activity assays and an in vivo mouse model of TAAD (induced by aminopropionitrile) were used to evaluate compound efficacy.
- Biolayer interferometry and AI/bioinformatics analyses were employed to investigate the binding mechanism of the lead compound.
Main Results:
- Crocin was identified as a potent inhibitor of MMP activity.
- Crocin significantly suppressed the occurrence and rupture of TAAD in a mouse model.
- Evidence suggests crocin directly binds to MMP2, inhibiting its activity.
- AI and experimental data confirmed crocin's therapeutic potential as an MMP inhibitor.
Conclusions:
- Crocin demonstrates significant therapeutic potential for treating thoracic aortic aneurysm and dissection.
- The study highlights the successful integration of AI and experimental approaches in drug discovery for complex diseases.
- Targeting MMPs with natural compounds like crocin offers a promising strategy for future TAAD pharmacotherapy.
Abstract:
Thoracic aortic aneurysm and dissection (TAAD) is a lethal cardiovascular condition without effective pharmaceutical therapy. Identifying novel drugs that target the key pathogenetic components is an urgent need. Bioinformatics analysis of pathological studies indicated "extracellular matrix organization" as the most significant functional pathway related to TAAD, in which matrix metallopeptidase (MMP) 2 and MMP9 ranked above other proteases. MMP1-14 were designated as the prototype molecules for docking against PubChem Compound Database using Surflex-Dock, and nine natural compounds were identified. Using a generic MMP activity assay and an aminopropionitrile (BAPN)-induced TAAD mouse model, we identified crocin as an effective MMP inhibitor, suppressing the occurrence and rupture of TAAD. Biolayer interferometry and AI/bioinformatics analyses indicated that crocin may inhibit MMP2 activity by direct binding. Possible binding sites were investigated. Overall, the integration of artificial intelligence and functional experiments identified crocin as an MMP inhibitor with strong therapeutic potential.
