In Vitro and In Silico Evaluation of Flavonoids as Human Plasma Kallikrein Inhibitors

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Abstract
: Plasma kallikrein (PKa), a serine proteinase in the kallikrein–kinin system, is involved in vascular inflammation and edema. In this work, three natural flavonoids, Fisetin, Morin, and Rutin, were screened as prospective human plasma kallikrein inhibitors and compared to the standard drug Sebetralstat by means of integrated in vitro and in silico assays. Chromogenic assay revealed concentration-dependent inhibition of plasma Kallikrein (IC50 = 300.13 µM for Fisetin, 377.36 µM for Morin, and 566.04 µM for Rutin). Satisfactory binding energies (–9.1, –8.6, and –7.5 kcal mol⁻¹ respectively) were also predicted, along with similar interaction patterns by molecular docking analyses. MD simulations demonstrated that Morin and Fisetin formed a stable complex, whereas Rutin induced local dynamic properties. The ADMET predictions revealed acceptable pharmacokinetic profiles for Fisetin and Morin, while Rutin showed low permeability. These results point to Fisetin and Morin as candidate natural scaffolds for selective inhibition of plasma kallikrein, with moderate in vitro potency but good in silico stability and pharmacokinetics. Additional confirmation in cellular models and structure-guided optimization of these flavonoid scaffolds are required to develop safer anti-inflammatory drugs that act on the kallikrein–kinin system.

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