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Anticancer potential of phytochemicals from Oroxylum indicum targeting Lactate Dehydrogenase A through bioinformatic approach - PubMed

  • ️Sat Jan 01 2022

Anticancer potential of phytochemicals from Oroxylum indicum targeting Lactate Dehydrogenase A through bioinformatic approach

Sheikh Sunzid Ahmed et al. Toxicol Rep. 2022.

Abstract

In recent years, small molecule inhibition of LDHA (Lactate Dehydrogenase A) has evolved as an appealing option for anticancer therapy. LDHA catalyzes the interconversion of pyruvate and lactate in the glycolysis pathway to play a crucial role in aerobic glycolysis. Therefore, in the current investigation LDHA was targeted with bioactive phytochemicals of an ethnomedicinally important plant species Oroxylum indicum (L.) Kurz. A total of 52 phytochemicals were screened against LDHA protein through molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) assay and molecular dynamics simulation to reveal three potential lead compounds such as Chrysin-7-O-glucuronide (-8.2 kcal/mol), Oroxindin (-8.1 kcal/mol) and Oroxin A (-8.0 kcal/mol). ADMET assay unveiled favorable pharmacokinetic, pharmacodynamic and toxicity properties for all the lead compounds. Molecular dynamics simulation exhibited significant conformational stability and compactness. MM/GBSA free binding energy calculations further corroborated the selection of top candidates where Oroxindin (-46.47 kcal/mol) was found to be better than Chrysin-7-O-glucuronide (-45.72 kcal/mol) and Oroxin A (-37.25 kcal/mol). Aldolase reductase and Xanthine dehydrogenase enzymes were found as potential drug targets and Esculin, the FDA approved drug was identified as structurally analogous to Oroxindin. These results could drive in establishing novel medications targeting LDHA to fight cancer.

Keywords: Cancer; Lactate Dehydrogenase A; MM/GBSA; Molecular docking; Molecular dynamics simulation; Oroxylum indicum.

© 2022 The Authors.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

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Graphical abstract
Fig. 1
Fig. 1

Workflow of the current study showing stepwise in silico screening of bioactive phytochemicals of O. indicum targeting Lactate Dehydrogenase A (LDHA).

Fig. 2
Fig. 2

Binding affinities of the investigated phytochemicals via virtual screening.

Fig. 3
Fig. 3

Three dimensional structures of the top selected lead compounds: (A). Chrysin-7-O-glucuronide; (B). Oroxindin and (C). Oroxin A.

Fig. 4
Fig. 4

Two-dimensional molecular interactions of three lead compounds with amino acid residues of the macromolecular receptor: (A). Chrysin-7-O-glucuronide; (B). Oroxindin and (C). Oroxin A.

Fig. 5
Fig. 5

Docked complexes with three dimensional molecular interactions between the macromolecular receptor and top selected candidates to show the surface of hydrogen bond donating and accepting regions in the target protein LDHA: (A). Chrysin-7-O-glucuronide; (B). Oroxindin and (C). Oroxin A.

Fig. 6
Fig. 6

Molecular dynamics simulation for 100 ns depicting RMSD, RMSF and Rg properties of the lead candidates Chrysin-7-O-glucuronide, Oroxindin and Oroxin A along with Sunitinib and apoprotein.

Fig. 7
Fig. 7

Molecular dynamics simulation for 100 ns depicting SASA values for the lead candidates Chrysin-7-O-glucuronide, Oroxindin and Oroxin A along with the control Sunitinib and apoprotein.

Fig. 8
Fig. 8

Number of hydrogen bonds formed between Lactate Dehydrogenase A and top three lead compounds along with the control Sunitinib.

Fig. 9
Fig. 9

Drug target class predicted for Chrysin-7-O-glucuronide (A), Oroxindin (B) and Oroxin A (C).

Fig. 10
Fig. 10

Two dimensional chemical structures of structurally similar analogs predicted for the top three phytochemicals: (A). Daidzin and (B). Troxerutin for Chrysin-7-O-glucuronide; (C). Esculin and (D). Icariin for Oroxindin; (E). Elsamitrucin and (F). Isoquercitrin for Oroxin A.

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