Identification of anti-cancer organometallic compounds by inhibition of BCL-2/Bax interactions

Abstract

Apoptosis is regulated by the BCL-2 family, which includes the anti-apoptotic and pro-apoptotic proteins (Bax, Bok, Bak, etc.). These proteins often interact in dimers and act as apoptotic switches. Anti-apoptotic proteins, such as BCL-2, block the functions of these pro-apoptotic proteins. The pro-apoptotic and anti-apoptotic protein-protein interactions must be inhibited to prevent tumor cells from escaping apoptosis. This method has been used to develop anticancer drugs by inhibiting BCL-2 with both natural and synthetic compounds. Metal-containing compounds were used as pharmaceuticals for human cancer patients for a long time, and cisplatin was the first candidate of this class. Drug design, however, needs to pay more attention to metal complexes. We have studied the X-ray crystal structure of the BCL-2 protein in detail and identified the hydrophobic nature of the site with two less solvent-accessible sites. Based on the hydrophobic nature of the compounds, 74 organometallic compounds with X-ray crystallographically characterized bioactivity (including anticancer activity) were selected from the Cambridge crystallographic database. For testing, molecular docking was used to determine which compound was most effective against the BCL-2 protein. Organometallic compounds (benzene)-chloro-(1-{[(9H-fluoren-2-yl)imino]methyl}naphthalen-2-olato)-ruthenium (2), (1-((1,1'-biphenyl)-4-yl)-2,3,4,5-tetramethylcyclopentadienyl)-chloro-(4,4'-dimethyl-2,2'-bipyridine)-rhodium hexafluorophosphate (37), (μ-1,1'-(butane-1,4-diyl)bis(3-oxy-2-methylpyridin-4(1H)-one))-dichloro-bis(pentamethyl-cyclopentadienyl)-di-rhodium tetrahydrate (46), (μ-1,1'-(butane-1,4-diyl)bis(3-oxy-2-methylpyridin-4(1H)-one))-dichloro-bis(pentamethyl-cyclopentadienyl)-di-iridium (47) etc are found to be important compounds in this study. The capability of different types of complex interactions was identified using Hirshfeld surface analysis of the complexes. A NCI plot was conducted to understand the nature of the interaction between complex amino acids and active-site amino acids. A DFT study was conducted to examine the stability and chemical reactivity of the selected complexes. Using this study, one suitable hydrophobic lead anti-cancer organometallic pharmaceutical was found that binds at the less solvent-accessible hydrophobic site of BCL-2.

Keywords: Cancer; Molecular docking; Molecular dynamics; Organometallic complexes; Protein-protein interactions.