Discovery of potential competitive inhibitors against With-No-Lysine kinase 1 for treating hypertension by virtualscreening, inverse pharmacophore-based lead optimization,and molecular dynamics simulations was written by Jonniya, N. A.;Sk, M. F.;Roy, R.;Kar, P.. And the article was included in SAR and QSAR in Environmental Research in 2022.Reference of 10083-24-6 This article mentions the following:
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 Hyperkalemic Hypertension, and thus WNK is considered a potential drug target. Herein, we have performed a highthroughput virtual screening of ∼11,000 compounds, mainly the natural phytochem. 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 pharmacol. 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 mol. dynamic simulations. Subsequently, the MMPBSA scheme (Mol. Mechanics Poisson Boltzmann Surface Area) suggested three phytochem. compounds C00000947, C00020451, and C00005031, with favorable 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. In the experiment, the researchers used many compounds, for example, (E)-4-(3,5-Dihydroxystyryl)benzene-1,2-diol (cas: 10083-24-6Reference of 10083-24-6).
(E)-4-(3,5-Dihydroxystyryl)benzene-1,2-diol (cas: 10083-24-6) belongs to alcohols. The oxygen atom of the strongly polarized O―H bond of an alcohol pulls electron density away from the hydrogen atom. This polarized hydrogen, which bears a partial positive charge, can form a hydrogen bond with a pair of nonbonding electrons on another oxygen atom. Secondary alcohols are easily oxidized without breaking carbon-carbon bonds only as far as the ketone stage. No further oxidation is seen except under very stringent conditions.Reference of 10083-24-6
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