Rational Design of Apigenin Derivatives as Potent Inflammatory Modulators for Improved Diabetic Wound Healing

AUTOR(I) / AUTHOR(S): Marko Antonijević, Sandra Jovičić Milić, Edina Avdović, Dejan Milenković, Zoran Marković

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DOI:  10.46793/ICCBIKG25.681A

SAŽETAK / ABSTRACT:

Chronic diabetic wounds present a significant therapeutic challenge, characterized by ongoing inflammation, disrupted angiogenesis, and excessive remodeling of the extracellular matrix. Flavonoids from grape skins have shown encouraging anti-inflammatory and antioxidant effects; however, their moderate potency restricts their wider therapeutic application. In this research, we utilized a systematic design strategy to create and assess new apigenin derivatives that exhibit enhanced pharmacological properties. A focused library of derivatives was screened against key protein targets involved in diabetic wound pathology, such as NF-κB, VEGFR-2, TGF-β1, and MMP-9, utilizing a combination of in silico based modifications and molecular docking techniques. The docking results demonstrated that derivatives showed significantly improved binding affinity in comparison to apigenin, especially with respect to MMP-9, suggesting potential inhibitory activity in the nanomolar to subnanomolar range. Comparable or slightly enhanced binding of VEGFR-2 was noted, alongside similar advancements in the modulation of NF-κB and TGF-β1. The results indicate that by optimizing the structure of apigenin, we can create derivatives that exhibit notably enhanced anti-inflammatory and anti- remodeling properties. The designed molecules effectively address both NF-κB-driven inflammation and MMP-9-mediated matrix degradation, offering a compelling basis for further validation as promising therapeutic candidates in the treatment of chronic diabetic wounds.

KLJUČNE REČI / KEYWORDS:

Diabetes, Wounds, Apigenin, Drug Design, Circular Economy

PROJEKAT / ACKNOWLEDGEMENT:

This research was supported by the Science Fund of the Republic of Serbia, #GRANT No. 11067, Unleashing Nature’s Potential: Using Grape Skin Extract and Sustainable Materials for Advanced Chronic Wound Therapy-GraSP_MAT.

LITERATURA / REFERENCES:

• Avdović, Edina, et al. Ultrasound-assisted extraction of bioactive phenolics from Marselan and Shiraz grape skins: A step toward circular economy in food and pharmaceutical industry. LWT, (2025) 117817.
• Chew, Joshua T., et al. Topical Bixa orellana for Postoperative Wound Healing: A Prospective Randomized Controlled Trial. Foot & Ankle Orthopaedics, 10.2 (2025) 24730114251345821.
• Antonijević, Marko, et , Nature’s Pharmacy: Grape Skin Polyphenols Target Diabetic Wounds, 13th Annual International Conference on Health & Medical Sciences 5-8 May 2025, Athens, Greece
• Polishchuk, Pavel.CReM: chemically reasonable mutations framework for structure generation. Journal of Cheminformatics 12.1, (2020) 28.
• Fu, Li, et al. ADMETlab 3.0: an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support. Nucleic acids research 52.W1, (2024) W422-W431.
• Daina, Antoine, Olivier Michielin, and Vincent Zoete. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports, 7.1, (2017) 42717.
• Valdés-Tresanco, Mario , et al. AMDock: a versatile graphical tool for assisting molecular docking with Autodock Vina and Autodock4. Biology direct, 15.1 (2020) 12.