Abstract:
Background: Houttuynia cordata Thunb. extract has shown programmed cell death induction in melanoma. Antagonism of the VEGF receptors (VEGFR) has been suggested as a potential mechanism of action due to its role in the progression of melanoma. Given the downsides of the current anti-VEGFR drugs, including lack of selectivity and unwanted side effects, the phytochemical constituents of Houttuynia cordata Thunb. were investigated for their inhibition of VEGFR using molecular docking simulations.
Objective: To investigate and identify the efficacy of potential orally-compatible phytochemical constituents that bind and inhibit the ATP binding sites of VEGFR1 and VEGFR2 using molecular docking simulations.
Materials and Method: The X-ray crystal structures of VEGFR1 and VEGFR2 were downloaded and prepared. A total of 74 phytochemical compounds in Houttuynia cordata Thunb. were constructed and energy minimized in 3D format and docked to the ATP binding sites of VEGFR1 and VEGFR2. Drug-like properties were calculated. This is followed by analysis of the binding modes, calculated docking scores and oral pharmacokinetics of potential candidates.
Results: Five compounds, luteolin, quercetin, isorhamnetin, apigenin, and kaempferol, were identified to have acceptable oral pharmacokinetics and docking scores, and were predicted in silico to have adequate VEGFR inhibition. Notably, apigenin and quercetin were predicted to have the best inhibitory action against VEGFR1 and VEGFR2, respectively, i.e., apigenin scored -9.148 kcal/mol against VEGFR1, and quercetin scored -9.945 kcal/mol against VEGFR2.
Conclusion: Luteolin, quercetin, isorhamnetin, apigenin, and kaempferol could serve as potential candidates for effective inhibition of the ATP binding site of VEGFR. In this light, these phytochemical constituents of Houttuynia cordata Thunb. are suggested as potential therapeutics for the treatment of melanoma through direct inhibition of VEGFR at the ATP
binding site. Specifically, apigenin and quercetin were predicted to be the strongest VEGFR1 and VEGFR2 inhibitors and are suggested for in vitro and in vivo drug tests.
