Targeting the gp130_D5 domain through pharmacophore modelling and structure-based virtual screening using natural plant products: A detailed molecular dynamics study for development of novel anti-cancer therapeutics

Abstract

An overexpression and upregulation has been observed in the activity of LIF in various cancers which leads to the worsening prognosis of numerous patients. Domain D5 of gp130 forms a crucial part of the downstream signalling pathway necessary for the activity of this cytokine. Due to the absence of any known inhibitors or previous studies conducted on this domain, this domain presents itself as a novel potential therapeutic target for the development of anti-cancer drugs. Here, an attempt has been made to discover one such potential lead drug candidate via the application of various computer-aided drug designing techniques. A natural plant products library was used along with known inhibitors of the STAT3 signalling pathway through which LIF exerts its activity. The ligand displaying the highest interaction with the target, a good docking score, and an optimal bioavailability was chosen. This ligand- ZINC02131250 forms a very strong complex with the target domain thatremains stable throughout the simulation period. Binding of the ligand to the target also results in an overall decrease in the domain's flexibility, free energy, and motion. Thus, this ligand can be taken for further testing using bioassays and then be used as a viable novel treatment for many cancer types.