Abstract

 
 
 
 Purpose: To search for novel gliomas targets and their inhibitors using a molecular docking approach.
 Methods: Quercetin multi-targeting potential was investigated against some of the emerging gliomas targets such as epidermal growth factor receptor (EGFR), ephrin type-A receptor 2 (EphA2), nicotinamide phosphoribosyltransferase (NMRPTase) and plasminogen activator inhibitor-1 (PAI-1). Crucial biochemical interaction of quercetin with these targets were analyzed using molecular docking study.
 Results: Quercetin interacted strongly via hydrogen bonding with important active sites consisting of amino acid residues of EphA2 and PAI-1, and showed binding energy of -7.44 and -7.38 kcal/mol, respectively. Some crucial active site amino acids involved in the interaction of known EphA2 and PAI-1 inhibitors (Alw-II-41-27 and ACT001) were common in quercetin interactions as well, and both inhibitors as well as quercetin did not violate Lipinski rules. Importantly, the quercetin-EphA2 and quercetin-PAI-1 complexes were stable as minimal fluctuations within the permissible limit were observed during a 20 ns trajectory performed on desmond simulation platform.
 Conclusion: Despite the fact that quercetin has been studied extensively against various cancer pathways, its transformation from a long-time bench candidate into bedside medications still needs further exploration. Nevertheless, the present predictive biochemical interaction analysis against emerging glioma targets might pave way for the design of novel therapeutic agents based on quercetin scaffolds.
 
 
 
Highlights
Glioblastoma (GBM) is considered a very common and highly aggressive primary malignant tumor of the brain in adult populations and it is often associated with poor patient prognosis and high morbidity/mortality [1]
The molecular docking interaction of ꞌQuercetinꞌ with ꞌEGFRꞌ revealed the involvement of twelve amino acid residues, i.e., Leu718, Val726, Ala743, Lys745, Thr790, Gln791, Leu792, Met793, Gly796, Cys797, Asp800 and Leu844 (Table 1)
Ligplot analysis showed that Lys745, Thr790, Gln791, Met793 and Cys797 amino acid residues of ꞌEGFR active siteꞌ were involved in hydrogen bonding, whereas, Leu718, Val726, Ala743, Leu792, Gly796 and Leu844
Summary
Glioblastoma (GBM) is considered a very common and highly aggressive primary malignant tumor of the brain in adult populations and it is often associated with poor patient prognosis and high morbidity/mortality [1]. Quercetin can induce apoptosis in tumour cells, and shows interaction with cyclindependent kinase (CDK)-4 and cyclin D1, the regulatory proteins of cell cycle that leads to activation of p53, induction of caspase-3 and caspase-9, and release of cytochrome c [6]. It has been suggested as a multi-target agent due to its PI3K inhibition potential that results in suppression of tumor growth [7]. It has been established that aglycone quercetin is associated with production of several pro-inflammatory mediators and microglia proliferation. Aglycone quercetin can be used as a possible adjuvant in treatment regimens owing to its modulatory effects on microglia profile [8]
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