Molecular Docking as a Therapeutic Approach for Targeting Cancer Stem Cell Metabolic Processes

Abstract

Cancer stem cells (CSCs) are subpopulation of cells which have been demonstrated in a variety of cancer models and involved in cancer initiation, progression, and development. Indeed, CSCs which seem to form a small percentage of tumor cells, display resembling characteristics to natural stem cells such as self-renewal, survival, differentiation, proliferation, and quiescence. Moreover, they have some characteristics that eventually can demonstrate the heterogeneity of cancer cells and tumor progression. On the other hand, another aspect of CSCs that has been recognized as a central concern facing cancer patients is resistance to mainstays of cancer treatment such as chemotherapy and radiation. Owing to these details and the stated stemness capabilities, these immature progenitors of cancerous cells can constantly persist after different therapies and cause tumor regrowth or metastasis. Further, in both normal development and malignancy, cellular metabolism and stemness are intricately linked and CSCs dominant metabolic phenotype changes across tumor entities, patients, and tumor subclones. Hence, CSCs can be determined as one of the factors that correlate to the failure of common therapeutic approaches in cancer treatment. In this context, researchers are searching out new alternative or complementary therapies such as targeted methods to fight against cancer. Molecular docking is one of the computational modeling methods that has a new promise in cancer cell targeting through drug designing and discovering programs. In a simple definition, molecular docking methods are used to determine the metabolic interaction between two molecules and find the best orientation of a ligand to its molecular target with minimal free energy in the formation of a stable complex. As a comprehensive approach, this computational drug design method can be thought more cost-effective and time-saving compare to other conventional methods in cancer treatment. In addition, increasing productivity and quality in pharmaceutical research can be another advantage of this molecular modeling method. Therefore, in recent years, it can be concluded that molecular docking can be considered as one of the novel strategies at the forefront of the cancer battle via targeting cancer stem cell metabolic processes.

Keywords: cancer; cancer stem cells; drug designing; metabolic processes; molecular docking.

FIGURE 1

Success rates of double combinations of the six relatively successful scoring functions in consensus scoring. All numbers are in percent (Wang et al., 2003).

FIGURE 2

Success rates of triple combinations of the six relatively successful scoring functions in consensus scoring. All numbers are in percent (R. Wang et al., 2003).

FIGURE 3

Mechanism of action of drugs analyzed by molecular docking on the metabolic processes of CSCs. The ligands and targets have been investigated by molecular docking. Nine effective drugs, including compound #25, andrographolide, mitoketoscins, emetine, cortistatin, solamargine, solasonine, tylophorine, and CIN-RM are known to affect the biological processes and signaling pathways of CSCs. 1) Compound #25 prevents the assembly of the Skp2-SCF complex by binding to Skp2. Hence, it inhibits two pathways including non-proteolytic K63-linked ubiquitination of Akt and ubiquitination and degradation of p27, which ultimately inhibit the development of tumor features. 2) Andrographolide increases intrinsic apoptosis in CSCs (especially in breast cancer) by inhibiting survivin, caspase-9, and caspase-3.3) Mitoketoscins stop the recycling of ketone bodies into Acetyl-CoA by inhibiting two proteins, including OXCT1 and ACAT1. Hence ATP production is stopped and oxidative mitochondrial metabolism in CSCs is inhibited. 4) Emetine and 5) Cortistatin, can target CSCs by binding to sonic Hh, Smo and, gli protein. 6) Solamargine can affect sonic hedgehog and gli proteins by its pharmacophores. 7) Solasonine and 8) Tylophorine modulate the Hh pathway by affecting gli proteins. 9) CIN-RM can lead to upstream inhibition of the Akt pathway and reduction of CSCs markers, which decrease the expression level of transcription factors involved in self-renewal, such as c-Myc, Nanog, Oct4, and Sox2. CIN-RM can inhibit mTOR pathway. Abbreviations: ATP, Adenosine triphosphate; CIN-RM, Hydroquinone 5-O-cinnamoyl ester of renieramycin M; CSCs, Cancer stem cells; Hh, Hedgehog; mTOR, Mammalian target of rapamycin; Smo, smoothened (Chan et al., 2013; Hongwiangchan et al., 2021; Jaitak, 2016; Liu et al., 2014; Madhunapantula et al., 2011; Ozsvari et al., 2017; Wanandi et al., 2020).