In Silico Identification and Biological Evaluation of Antioxidant Food Components Endowed with Human Carbonic Anhydrase IX and XII Inhibition

Abstract

The tumor-associated isoenzymes hCA IX and hCA XII catalyze the hydration of carbon dioxide to bicarbonate and protons. These isoforms are highly overexpressed in many types of cancer, where they contribute to the acidification of the tumor environment, promoting tumor cell invasion and metastasis. In this work, in order to identify novel dual hCA IX and XII inhibitors, virtual screening techniques and biological assays were combined. A structure-based virtual screening towards hCA IX and XII was performed using a database of approximately 26,000 natural compounds. The best shared hits were submitted to a thermodynamic analysis and three promising best hits were identified and evaluated in terms of their hCA IX and XII inhibitor activity. In vitro biological assays were in line with the theoretical studies and revealed that syringin, lithospermic acid, and (-)-dehydrodiconiferyl alcohol behave as good hCA IX and hCA XII dual inhibitors.

Uncovering Novel Capsaicin Inhibitory Activity towards Human Carbonic Anhydrase Isoforms IX and XII by Combining In Silico and In Vitro Studies

“…They have a crucial pathophysiological role in various human diseases, e.g., glaucoma, hemolytic anemia, osteoporosis, neurological disorders, and particularly in hypoxic cancers. To date, eight different families of CAs have been discovered (α-CAs, β-CAs, γ-CAs, δ-CAs, ζ-CAs, θ-CAs,η-Cas, and ι-CAs) [17]. According to catalytic activity, tissue distribution, and subcellular localization, human (h) CAs belonging to the α-family are present in 15 different isoforms.…”

“…Both isoforms have been validated as markers of cancer proliferation and invasion in many hypoxic tumors, and their targeted inhibition seems to impair the pH of the tumor microenvironment, with a significant reduction in malignant cells' progression and tendency to metastasize [19]. Although sulfonamide-based hCA IX and hCA XII inhibitors showed the best results as anticancer agents [20], several natural compounds have also demonstrated significant hCA IX and hCA XII inhibitory activity, such as molecules with phenol moiety (lithospermic acid, (-)-dehydrodiconiferyl alcohol and syringin), or coumarins and psoralens analogs [17,21] (Figure 1). [17].…”

“…Although sulfonamide-based hCA IX and hCA XII inhibitors showed the best results as anticancer agents [20], several natural compounds have also demonstrated significant hCA IX and hCA XII inhibitory activity, such as molecules with phenol moiety (lithospermic acid, (-)-dehydrodiconiferyl alcohol and syringin), or coumarins and psoralens analogs [17,21] (Figure 1). [17]. According to catalytic activity, tissue distribution, and subcellular localization, human (h) CAs belonging to the α-family are present in 15 different isoforms.…”

Natural Products Extracted from Fungal Species as New Potential Anti-Cancer Drugs: A Structure-Based Drug Repurposing Approach Targeting HDAC7

“…In parallel to the repurposing paradigm, the application of in silico techniques for identifying new hit compounds is a very profitable approach [31], reducing cost and time of research-associated activities [32][33][34][35]. In particular, structure-based virtual screening (SBVS) is a powerful in silico tool for the identification of novel bioactive ligands and is very useful in predicting the best interaction between ligands and molecular targets [36][37][38][39][40][41][42][43][44][45][46].…”

In Silico Food-Drug Interaction: A Case Study of Eluxadoline and Fatty Meal

“…Nowadays, computational techniques represent powerful tools in the pharmaceutical industry and academia [18,19]. Generally, they are widely applied to drug discovery in different applications fields, but they are useful also for the deep comprehension of the ligand selectivity and the targets folding [20][21][22][23][24][25][26][27][28][29][30][31][32]. However, there is a considerable need to be able to predict the clinical behavior of drugs in order to optimize pharmacological treatments by increasing their efficacy and decrease the frequency and/or severity of adverse events.…”