A computational analysis of the binding free energies of apoptosis signal-regulating kinase 1 inhibitors from different chemotypes

ABSTRACT

Apoptosis signal-regulating kinase 1 (ASK1) has recently emerged as an attractive molecular target for pharmaceutical intervention. Several classes of small-molecular ASK1 inhibitors have been identified. In this article, we analysed the binding of small-molecular inhibitors from different chemotypes with ASK1 using molecular dynamic simulations. The umbrella sampling technique was used to calculate the binding free energy (ΔG) for these compounds with ASK1 ATP-binding pocket. According to the obtained results, umbrella sampling gave correct ranking of the binding affinities for investigated inhibitors relative to their experimental pIC₅₀ values and can be useful for further structure-based design of ASK1 inhibitors to accelerate lead optimisation.

Trial registration: ClinicalTrials.gov identifier: NCT02466516..

KEYWORDS:

• Apoptosis signal-regulating kinase 1
• ASK1
• inhibitor
• umbrella sampling
• binding free energy

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Grant of the State Fund for Fundamental Researches (SFFR F63) in Ukraine [grant number 0116U006538] and by the Grant of the National Academy of Sciences of Ukraine [grant number 0112U000254.].