Molecular docking studies of 3-bromopyruvate and its derivatives to metabolic regulatory enzymes: Implication in designing of novel anticancer therapeutic strategies

Abstract

Altered metabolism is an emerging hallmark of cancer, as malignant cells display a mammoth up-regulation of enzymes responsible for steering their bioenergetic and biosynthetic machinery. Thus, the recent anticancer therapeutic strategies focus on the targeting of metabolic enzymes, which has led to the identification of specific metabolic inhibitors. One of such inhibitors is 3-bromopyruvate (3-BP), with broad spectrum of anticancer activity due to its ability to inhibit multiple metabolic enzymes. However, the molecular characterization of its binding to the wide spectrum of target enzymes remains largely elusive. Therefore, in the present study we undertook in silico investigations to decipher the molecular nature of the docking of 3-BP with key target enzymes of glycolysis and TCA cycle by PatchDock and YASARA docking tools. Additionally, derivatives of 3-BP, dibromopyruvate (DBPA) and propionic acid (PA), with reported biological activity, were also investigated for docking to important target metabolic enzymes of 3-BP, in order to predict their therapeutic efficacy versus that of 3-BP. A comparison of the docking scores with respect to 3-BP indicated that both of these derivatives display a better binding strength to metabolic enzymes. Further, analysis of the drug likeness of 3-BP, DBPA and PA by Lipinski filter, admetSAR and FAF Drug3 indicated that all of these agents showed desirable drug-like criteria. The outcome of this investigation sheds light on the molecular characteristics of the binding of 3-BP and its derivatives with metabolic enzymes and thus may significantly contribute in designing and optimizing therapeutic strategies against cancer by using these agents.

Global energy and molecular interactions between Pazopanib, Axitinib and Sorafenib anticancer drugs with vascular endothelial growth factor

“…The negative value of the binding energy shows that the pozapanib can selectively inhibit VEGF. This is consistent with the work of Yadav et al (2017).…”

Identification of Dietary Molecules as Therapeutic Agents to Combat COVID-19 Using Molecular Docking Studies

“…Preparation of grid mapsfor each protein was performed by inputting binding site coordinates which were retrieved by Discovery Studio 3.0 visualizer and Grid Box X, Y, and Z dimensions changed from default to 50×50×50. Docking was performed by Lamarckian genetic algorithm and empirical scoring function by using flexible method.Alldocking results were analyzed with the help of AD4 analyze option to find out the binding energy (BE) and inhibitory constant (Ki) of the ligand with a particular target protein.Visualization of structural complex of ligand and protein was done with the help of Discovery Studio 3.0 Client[14,15].…”

Topical 3-bromopyruvate is a novel targeted therapy for melanoma in a preclinical model

“…Accordingly, topical administration of 3BP is not only proved to be a promising strategy for treatment of unresectable melanoma, but also reasoned that trials for testing the efficacy of topical 3BP are possibly warranted for other skin cancers. It is also a challenge for future studies to develop other strategies to deliver 3BP by a nanovehicle [36][37][38][39] or to develop more efficient derivatives [40][41][42]. Further studies will thus be required to clarify the adverse effects of 3-bromopyruvate on normal cells or tissues of various organs.…”