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

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.