Discovery of potential competitive inhibitors against With-No-Lysine kinase 1 for treating hypertension by virtual screening, inverse pharmacophore-based lead optimization, and molecular dynamics simulations

ABSTRACT

The With-No-Lysine (WNK) has received attention because of its involvement in hypertension. Genetic mutation in the genes of WNK, leading to its overexpression, has been reported in Familial Hyperkalaemic Hypertension, and thus WNK is considered a potential drug target. Herein, we have performed a high-throughput virtual screening of ~11,000 compounds, mainly the natural phytochemical compounds and kinase inhibitory libraries, to find potential competitive inhibitors against WNK1. Initially, candidates with a docking score of ~ −10.0 kcal/mol or less were selected to further screen their good pharmacological properties by applying absorption, distribution, metabolism, excretion, and toxicity (ADMET). Finally, six docked compounds bearing appreciable binding affinities and WNK1 selectivity were complimented with 500 ns long all-atom molecular dynamic simulations. Subsequently, the MMPBSA scheme (Molecular Mechanics Poisson Boltzmann Surface Area) suggested three phytochemical compounds, C00000947, C00020451, and C00005031, with favourable binding affinity against WNK1. Among them, C00000947 acts as the most potent competitive inhibitor of WNK1. Further, inverse pharmacophore-based lead optimization of the C00000947 leads to one potential compound, meciadanol, which shows better binding affinity and specificity than C00000947 towards WNK1, which may be further exploited to develop effective therapeutics against WNK1-associated hypertension after in vitro and in vivo validation.

KEYWORDS:

• Hypertension
• competitive inhibitor
• With-No-Lysine kinase
• virtual screening
• molecular dynamics

Disclosure statement

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

Data availability statement

The data that support the findings of this study are available from the corresponding author (PK) upon reasonable request.

Ethics statement

There is no human or animal experiment in this study.

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2021.2023218

Additional information

Funding

This work was supported by the Department of Biotechnology, Govt. of India [grant number BT/RLF/Re-entry/40/2014, DBT-Ramalingaswami Re-entry Fellowship] and the Department of Science and Technology, Govt. of India [grant number DST/NSM/R&D_HPC_Applications/2021/03.18].