Structure-Guided Approach to Discover Tuberosin as a Potent Activator of Pyruvate Kinase M2, Targeting Cancer Therapy

Abstract

Metabolic reprogramming is a key attribute of cancer progression. An altered expression of pyruvate kinase M2 (PKM2), a phosphotyrosine-binding protein is observed in many human cancers. PKM2 plays a vital role in metabolic reprogramming, transcription and cell cycle progression and thus is deliberated as an attractive target in anticancer drug development. The expression of PKM2 is essential for aerobic glycolysis and cell proliferation, especially in cancer cells, facilitating selective targeting of PKM2 in cell metabolism for cancer therapeutics. We have screened a virtual library of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database of Indian medicinal plants to identify potential activators of PKM2. The initial screening was carried out for the physicochemical properties of the compounds, and then structure-based molecular docking was performed to select compounds based on their binding affinity towards PKM2. Subsequently, the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties, PAINS (Pan-assay interference compounds) patterns, and PASS evaluation were carried out to find more potent hits against PKM2. Here, Tuberosin was identified from the screening process bearing appreciable binding affinity toward the PKM2-binding pocket and showed a worthy set of drug-like properties. Finally, molecular dynamics simulation for 100 ns was performed, which showed decent stability of the protein-ligand complex and relatival conformational dynamics throughout the trajectory. The study suggests that modulating PKM2 with natural compounds is an attractive approach in treating human malignancy after required validation.

Integrating network pharmacology and experimental verification to decipher the multitarget pharmacological mechanism of Cinnamomum zeylanicum essential oil in treating inflammation

“…This might be due to the fact that compounds present in essential oil are mostly volatile constituents, whereas that in extracts are usually non-volatile compounds. It is imperative to carry out pharmacokinetic parameter screening of herbal medicine to obtain active constituents [ 37 ]. After screening compounds for drug-likeness (Lipinski's rule) and bioavailability score (Abbott), 52 active compounds were retrieved.…”

“…The molecular docking score indicated that the significant node (benzyl benzoate), which had a high degree obtained from network analysis, had the strongest affinity with probable target genes. Additionally, according to prior studies, benzyl benzoate substantially reduces inflammation of the skin [ 37 ]. This finding suggests that one or more compounds may interact with many target proteins instead of just one molecule and one target protein.…”

Integrated Network Pharmacology, Molecular Docking, Molecular Simulation, and In Vitro Validation Revealed the Bioactive Components in Soy-Fermented Food Products and the Underlying Mechanistic Pathways in Lung Cancer

“…Computational methods such as molecular dynamics (MDs) are used to understand how ligands behave in the binding pocket of receptors based on their time-dependent conformational stability. Several studies have demonstrated its practical application in identifying new inhibitors in a number of applications [ 33 , 34 , 35 , 36 ]. In this study, MD analyses were performed with Gromacs version 2019.4 [ 37 ].…”

Pyruvate Kinase M2 Accelerates Cutaneous Wound Healing via Glycolysis and Wnt/β-Catenin Signaling

“…There are four different isoforms of PK: PKL, PKR, PKM1, and PKM2, which determine the rate of glycolysis [ 11 , 12 ]. Among them, pyruvate kinase M2 (PKM2) plays an important role in cell proliferation and is mainly expressed in the regenerated region of damaged tissues [ 10 , 13 ]. In addition, PKM2 promotes angiogenesis by facilitating endothelial cell migration and extracellular matrix (ECM) attachment [ 14 , 15 ].…”