Structural and molecular insights from dual inhibitors of EGFR and VEGFR2 as a strategy to improve the efficacy of cancer therapy.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor 2 (VEGFR2) are known as valid targets for cancer therapy. Overexpression of EGFR induces uncontrolled cell proliferation and VEGF expression triggering angiogenesis via VEGFR2 signaling. On the other hand, VEGF expression independent of EGFR signaling is already known as one of the mechanisms of resistance to anti-EGFR therapy. Therefore, drugs that act as dual inhibitors of EGFR and VEGFR2 can be a solution to the problem of drug resistance and increase the effectiveness of therapy. In this review, we summarize the relationship between EGFR and VEGFR2 signal transduction in promoting cancer growth and how their kinase domain structures can affect the selectivity of an inhibitor as the basis for designing dual inhibitors. In addition, several recent studies on the development of dual EGFR and VEGFR2 inhibitors involving docking simulations were highlighted in this paper to provide some references such as pharmacophore features of inhibitors and key residues for further research, especially in computer-aided drug design.

Antihyperlipidemic mechanisms of a formula containing Curcuma xanthorrhiza, Sechium edule, and Syzigium polyanthum: In silico and in vitro studies.

Herbal medicines are multi-component and can exhibit synergistic effects in the treatment of diseases. Sechium edule, Syzigium polyanthum, and Curcuma xanthorrhiza have been used in traditional medicine to reduce serum lipid levels. However, the molecular mechanism was not described clearly, especially as a mixture. Thus, we performed a network pharmacology study combined with molecular docking to find a rational explanation regarding the molecular mechanisms of this antihyperlipidemic formula. According to the network pharmacology study, we predicted that this extract mixture would act as an antihyperlipidemic agent by modulating several pathways including insulin resistance, endocrine resistance, and AMP-activated protein kinase (AMPK) signaling pathway. Based on the topology parameters, we identified 6 significant targets that play an important role in reducing lipid serum levels: HMG-CoA reductase (HMGCR), peroxisome proliferator-activated receptor alpha (PPARA), RAC-alpha serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR), matrix metalloproteinase-9 (MMP9), and tumor necrosis factor-alpha (TNF). Meanwhile, 8 compounds: ß-sitosterol, bisdesmethoxycurcumin, cucurbitacin D, cucurbitacin E, myricetin, phloretin, quercitrin, and rutin were the compounds with a high degree, indicating that these compounds have a multitarget effect. Our consensus docking study revealed that HMGCR was the only protein targeted by all potential compounds, and rutin was the compound with the best consensus docking score for almost all targets. The in vitro study revealed that the extract combination could inhibit HMGCR with an IC50 value of 74.26 µg/mL, indicating that HMGCR inhibition is one of its antihyperlipidemic mechanisms.