Evodiamine and Rutaecarpine as Potential Anticancer Compounds: A Combined Computational Study

Abstract

Evodiamine (EVO) and rutaecarpine (RUT) are the main active compounds of the traditional Chinese medicinal herb Evodia rutaecarpa. Here, we fully optimized the molecular geometries of EVO and RUT at the B3LYP/6-311++G (d, p) level of density functional theory. The natural population analysis (NPA) charges, frontier molecular orbitals, molecular electrostatic potentials, and the chemical reactivity descriptors for EVO and RUT were also investigated. Furthermore, molecular docking, molecular dynamics simulations, and the analysis of the binding free energies of EVO and RUT were carried out against the anticancer target topoisomerase 1 (TOP1) to clarify their anticancer mechanisms. The docking results indicated that they could inhibit TOP1 by intercalating into the cleaved DNA-binding site to form a TOP1–DNA–ligand ternary complex, suggesting that they may be potential TOP1 inhibitors. Molecular dynamics (MD) simulations evaluated the binding stability of the TOP1–DNA–ligand ternary complex. The calculation of binding free energy showed that the binding ability of EVO with TOP1 was stronger than that of RUT. These results elucidated the structure–activity relationship and the antitumor mechanism of EVO and RUT at the molecular level. It is suggested that EVO and RUT may be potential compounds for the development of new anticancer drugs.

Experimental and computational study on anti-gastric cancer activity and mechanism of evodiamine derivatives

“…As shown in Figure 3 , we plotted the binding models of EVO-1 and EVO-6 with TOP1. The binding conformations of EVO-1 and EVO-6 with TOP1 were very similar, which is consistent with the previous predicted binding mode of EVO with TOP1 ( Liu et al, 2022 ). Despite the nonplanar structure of EVO and its derivatives, they can still bind to the active site of TOP1.…”

“…For compound EVO-4, the optimized structure was consistent with the X-ray structure (Nie et al, 2020). The optimized geometries of other derivatives were almost nonplanar, similar to the optimized geometry of EVO (Liu et al, 2022).…”

Nanoparticle-mediated diagnosis, treatment, and prevention of breast cancer

“…It is basically an indolequinone alkaloid extracted from Evodia rutaecarpa , a multi-purpose herb native to China. 22 The mechanism of action of EVO includes the activation of caspases, which are critical enzymes responsible for executing apoptosis. 22 However, despite its potent anticancer efficacy, the clinical application of EVO is hindered by its limited pharmacokinetics, including poor aqueous solubility, diminished gastrointestinal absorption, and reduced oral bioavailability.…”

“… 22 The mechanism of action of EVO includes the activation of caspases, which are critical enzymes responsible for executing apoptosis. 22 However, despite its potent anticancer efficacy, the clinical application of EVO is hindered by its limited pharmacokinetics, including poor aqueous solubility, diminished gastrointestinal absorption, and reduced oral bioavailability. 22 Additionally, EVO administration is associated with adverse effects ranging from gastrointestinal disturbances (diarrhoea, constipation, anorexia, and stomach discomfort) to severe toxicities (hepatotoxicity and cardiotoxicity) under high doses or prolonged usage.…”

Understanding the Exchange Interaction between Paramagnetic Metal Ions and Radical Ligands: DFT and Ab Initio Study on Semiquinonato Cu(II) Complexes

“…It is now well established that theoretical methods are an efficient multipurpose tool for chemistry, biochemistry, and material science. Recent scientific efforts have shown that they can help us understand various phenomena, for example, reaction mechanisms or reactivity [ 35 , 36 , 37 , 38 ], electron density distribution [ 39 , 40 , 41 ], and elusive structure of complex biochemical systems or radical centers [ 42 , 43 , 44 ], anticancer [ 35 , 45 ] and antioxidant properties [ 46 , 47 , 48 , 49 , 50 , 51 ], soot formation [ 52 ] or pesticide decomposition [ 53 ]. The exchange coupling between paramagnetic centers has been a subject of such investigations at the density functional theory (DFT) and ab initio levels, but these studies were mainly limited to the interaction between metallic centers [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ].…”