Integrated computational approach identifies potential inhibitors of ASK1-(JNK/P38) interaction signaling: new insights into cancer therapeutics

Cancers are characterized by the aberrant expression of certain genes that trigger a cascade of molecular events that culminate in dysregulated cell division. Consequently, the inhibition of the products of these expressedgenes has emerged as a rational approach in cancer therapy. The apoptosis signal-regulating kinase 1 (ASK1) protein, encoded by the mitogen-activated protein kinase kinase kinase 5 (MAP3K5) gene, plays pertinent roles in the mediation of cell death induced by stress and inflammation, andis often found at elevated levels in cancer. Consequently, it has emerged as a molecular target for the development of potential chemotherapeutics through identification of selective inhibitors. However, there is still dearth of ASK1 inhibitors in clinical use. Hence, molecular modelling approaches were employed in this study to discover potential ASK1 inhibitors from phytochemicals. Twenty-five phytocompounds from four medicinal plants were tested for their inhibitory prowess via molecular docking. Interestingly, all the compounds exhibited promising inhibitory potentials for ASK1. However, further subjection to filtering procedures via different pipelines including drug-likeness evaluation, pharmacokinetics screening, toxicity profiling, and better affinities compared to the approved inhibitor resulted in three hit compounds namely ellagic acid, luteolin, and kaempferol with suitable properties. Profiling of the interactions formed between the hit\compounds and the targets revealed several interactions that were not present in that of the approved inhibitor, while molecular dynamics (MD) simulation revealed the complexes formed as stable. Conclusively, this study identified three compounds with ASK1 inhibitory potentials that are worthy of further exploration in in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma

Automated summary

Cancers are characterized by aberrant gene expression that leads to dysregulated cell division. Inhibiting these gene products has become a rational approach in cancer therapy. The protein ASK1, encoded by the MAP3K5 gene, is often found at elevated levels in cancer and has emerged as a potential target for developing chemotherapeutics. This study employed molecular modelling approaches to identify potential ASK1 inhibitors from phytochemicals. Three hit compounds, ellagic acid, luteolin, and kaempferol, showed promising inhibitory potentials and had suitable properties for further exploration in in vitro and in vivo studies.