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Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey.

ABSTRACT: Owing to the growing hardware capabilities and the enhancing efficacy of computational methodologies, computational chemistry approaches have constantly become more important in the development of novel anticancer metallodrugs. Besides traditional Pt-based drugs, inorganic and organometallic complexes of other transition metals are showing increasing potential in the treatment of cancer. Among them, Au(I)- and Au(III)-based compounds are promising candidates due to the strong affinity of Au(I) cations to cysteine and selenocysteine side chains of the protein residues and to Au(III) complexes being more labile and prone to the reduction to either Au(I) or Au(0) in the physiological milieu. A correct prediction of metal complexes' properties and of their bonding interactions with potential ligands requires QM computations, usually at the ab initio or DFT level. However, MM, MD, and docking approaches can also give useful information on their binding site on large biomolecular targets, such as proteins or DNA, provided a careful parametrization of the metal force field is employed. In this review, we provide an overview of the recent computational studies of Au(I) and Au(III) antitumor compounds and of their interactions with biomolecular targets, such as sulfur- and selenium-containing enzymes, like glutathione reductases, glutathione peroxidase, glutathione-S-transferase, cysteine protease, thioredoxin reductase and poly (ADP-ribose) polymerase 1.

SUBMITTER: Tolbatov I

PROVIDER: S-EPMC8707411 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In this study, four new Mn(II), Fe(III), and Cr(III) complexes with two Schiff base ligands namely, 4-bromo-2-[(E)-{[4-(2-hydroxyethyl)phenyl]imino}methyl]phenol (HL1) and 2-[(E)-{[4-(2-hydroxyethyl)phenyl]imino}methyl]-4-methoxy phenol (HL2) have been synthesized and characterized. Different analytical and spectral methods have been used to characterize the ligands and their complexes. General formulas of [M(L)Cl2(H2O)2] for FeL1, CrL1 and CrL2, and [M(L)Cl(H2O)3] for MnL2 were proposed. HOMO and LUMO energies, as well as the electrical characteristics, have been calculated using DFT/B3LYP calculations with Gaussian 09 program. The optimized lowest energy configurations of the complexes are proven. The disc diffusion technique was used to test the pharmacological activities' antibacterial efficacy against diverse bacterial and fungus species. The MTT technique was used to assess the in vitro cytotoxicity of the ligands and their metal complexes on the Hep-G2 human liver carcinoma cell line and the MCF-7 human breast cancer cell line. All compounds displayed better activity compared to the free ligands. MnL2 complex showed predominant activity when compared to the other complexes with an IC50 value of 2.6 ± 0.11 μg/ml against Hep-G2, and against MCF-7 the IC50 value was 3.0 ± 0.2 μg/ml which is less than the standard drug cisplatin (4.0 μg/ml). UV-vis electronic spectrum and gel electrophoresis techniques have been used to investigate the compounds' affinity to bind and cleavage CT-DNA. The interaction's binding constants, or Kb, have been identified, and it was discovered that the new complexes' binding affinities are in the order of FeL1 > MnL2 > CrL2 > CrL1, and the binding mechanism has been suggested. To assess the kind of binding and binding affinity of the investigated drugs with human DNA, a molecular docking study was carried out (PDB:1bna). The acquired results supported the intercalation binding mechanism proposed in the experimental part and revealed that complexes may be inserted into the DNA molecule to stop DNA replication. According to ADMET data, the synthesized compounds have a high bioavailability profile and their physicochemical and pharmacological features remained within Lipinski's RO5 predicted limitations.

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Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey.

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