Ganoderic acid targeting multiple receptors in cancer: in silico and in vitro study

Abstract

Receptor tyrosine kinases (RTKs) are transmembrane high-affinity surface receptors responsible for cell migration, adhesion, apoptosis, metabolism, and cell proliferation activities in various cancers. Minute aberration in the RTK signaling modulates the downstream signaling pathways that results in cancer. Ganoderic acid is a triterpene isolated from Ganoderma lucidum, which is renowned for its therapeutics effect, especially in cancer. The present study discusses receptor-based molecular docking of insulin receptor (IR), insulin-like growth factor receptor 1 (IGFR-1), vascular endothelial growth factor receptor-1 (VEGFR-1), vascular endothelial growth factor receptor-2 (VEGFR-2), and estrogen receptor (ER) with 50 isoforms of ganoderic acid along with natural inhibitors. These receptors were assessed for toxicity (ADMET) by using Maestro 9.6 (Schrödinger Inc). The calculated docking free energy yielded an excellent dock score for the ganoderic acid when docked with proteins IR, IGFR-1, VEGFR-1, VEGFR-2, and ER, suggesting its potential in combating cancer. Protein-ligand profile highlighted the binding interactions comprising lipophilic, hydrogen bonding, pi-pi stacking interactions, and noncovalent bonding which play a pivotal role in targeting cancer. In silico studies revealed structure of ganoderic acid A as best isoforms among 50 isoforms which exhibits biological activity in liver cancer cells. Ganoderic acids A significantly decrease the viability, proliferation, and oxidative stress in a dose-dependent manner in liver cancer cells.

B-glucans from Grifola frondosa and Ganoderma lucidum in breast cancer: an example of complementary and integrative medicine

“…G. lucidum modulates the signaling of cancer cells by inhibiting NF-κB nuclear translocation RAS-mitogen-activated protein kinase (MAPK) activation and apoptosis processes. In particular, GA, a triterpene isolated from G. lucidum , strongly inhibits the activation of transmembrane surface receptors (RTKs) [ 49 ], which modulate intracellular downstream signals responsible for cell adhesion, proliferation, migration, apoptosis, and metabolism in various cancer cells. Specifically, 50 isoforms of GA were studied in relation to specific inhibition of RTKs such as insulin receptor (IR), insulin-like growth factor (IGFR), VEGFR1, VEGFR2, and estrogen receptor in liver cancer cells (Figure 4 ).…”

Biosynthesis of a ganoderic acid in Saccharomyces cerevisiae by expressing a cytochrome P450 gene from Ganoderma lucidum

“…Ganoderma products are nowadays consumed worldwide as a health tonic and dietary supplement with its current annual sales over US$2.5 billion (Li et al, ). Ganoderic acids (GAs), a group of highly oxygenated lanostane‐type triterpenoids, are well recognized as a main group of unique bioactive compounds in the medicinal mushroom (Bishop et al, ; Li et al, ; Shiao, ; Tang, Liu, Zhao, Wei, & Zhong, ; Xiao & Zhong, ; Zhong & Xiao, ); and several individual GAs have been reported to possess important biological and pharmacological activities including antitumor, anti‐metastasis, and anti‐HIV effects in both in vitro and in vivo studies (Bishop et al, ; Gill et al, ; Sato, Zhang, Ma, & Hattori, ; Tang et al, ).…”

“…2003 ;Tang, Liu, Zhao, Wei, & Zhong, 2006;Xiao & Zhong, 2016;Zhong & Xiao, 2009); and several individual GAs have been reported to possess important biological and pharmacological activities including antitumor, anti-metastasis, and anti-HIV effects in both in vitro and in vivo studies (Bishop et al, 2015;Gill et al, 2016;Sato, Zhang, Ma, & Hattori, 2009;Tang et al, 2006).…”

Ganoderic acid A is the effective ingredient of Ganoderma triterpenes in retarding renal cyst development in polycystic kidney disease

“…Several studies have shown that Ganoderic acids (GA) are the major components of GT [ 14 ] and exhibit extraordinary pharmacological activities, especially anticancer activity, that affect multiple signaling pathways involved in the pathogenesis of ADPKD [ 15 – 18 ]. Hence, in this study, 12 monomers were isolated from GA, and their anti-cyst activity was assessed using in vitro and in vivo cyst models [ 19 ].…”