Cheminformatics Analysis of Dynamic WNK‐Inhibitor Interactions

Kuenemann, Mélaine A.; Fourches, Denis

doi:10.1002/minf.201700138

Cited by 8 publications

(4 citation statements)

References 46 publications

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“…To understand these interactions between kinase and the ligand (WNK463), the lowest energy structures obtained from the MD simulations were considered. Kuenemann and Fourches 53 had observed various hydrogen bond and hydrophobic interactions such as between imidazole nitrogen of ligand and backbone Met 304 and with Asp 368 and Leu 369 , as well as multiple hydrophobic interactions such as Val 235 , Ala 248 , Phe 256 , Leu 272 , Leu 299 , Leu 371 , and Phe 356 . We also have observed the similar interactions between imidazole nitrogen and the backbone Met 304 .…”

Section: Resultsmentioning

confidence: 99%

Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations

Jonniya

Kar

2019

ACS Omega

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The With-No-Lysine (WNK) kinase is considered to be a master regulator for various cation-chloride cotransporters involved in maintaining cell-volume and ion homeostasis. Here, we have investigated the phosphorylation-induced structural dynamics of the WNK1 kinase bound to an inhibitor via atomistic molecular dynamics simulations. Results from our simulations show that the phosphorylation at Ser382 could stabilize the otherwise flexible activation loop (A-loop). The intrahelix salt-bridge formed between Arg264 and Glu268 in the unphosphorylated system is disengaged after the phosphorylation, and Glu268 reorients itself and forms a stable salt-bridge with Arg348. The dynamic cross-correlation analysis shows that phosphorylation diminishes anticorrelated motions and increases correlated motions between different domains. Structural network analysis reveals that the phosphorylation causes structural rearrangements and shortens the communication path between the αC-helix and catalytic loop, making the binding pocket more suitable for accommodating the ligand. Overall, we have characterized the structural changes in the WNK kinase because of phosphorylation in the A-loop, which might help in designing rational drugs.

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Section: Resultsmentioning

confidence: 99%

Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations

Jonniya

Kar

2019

ACS Omega

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“…Cells showed viability 98% were incubated with different concentration of primary hits to the 96 well plate for 24 h followed by 4 h incubation with MTT 5 mg/ml. The absorbance was recorded at 580 nm using Synergy/HTX MultiScan reader (BioTek) [23]. Experiments were carried out in triplicate and the Lethal dose (LD 50 ) of each primary hits was calculated and the safety index (SI) was calculated.…”

Section: Resultsmentioning

confidence: 99%

Docking predictions based Plasmodium falciparum phosphoethanolamine methyl transferase inhibitor identification and in-vitro antimalarial activity analysis

Singh

Mansuri

Vijay³

et al. 2019

BMC Chemistry

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The increased multidrug resistance among antimalarial drugs produces the urgency of potent anti malarial to combat resistant malaria and the malaria burden worldwide. The protein which may prevent the growth or transmission of malaria parasite may be the great target for rational drug designing. Plasmodium falciparum phosphoethanolamine methyltransferase ( Pf pmt) absent in human catalyzes triple methylation of ethanolamine into phosphocholine for phosphatidylcholine biosynthesis from serine decarboxylation phosphoethanolamine methyltransferase pathway for the membrane development at asexual as well as sexual stages of parasite. The Plasmodium requires production of membrane rapidly for growth and multiplication. Hence, the phosphoethanolamine methyltransferase of Plasmodium falciparum was selected as drug target for rational drug designing. Using Discovery studio 3.5 software the library of zinc compounds was screened against target and analyzed. The compounds with better druglike properties and docking affinity and binding interaction for target protein were procured for in vitro analysis against Plasmodium falciparum culture (IC 50 ). Compounds ZINC02103914 and ZINC12882412 were found to have good druglike properties and affinity for Pf pmt also inhibited P. falciparum growth at very low µM IC 50 concentration 3.0 µM and 2.1 µM respectively also found nontoxic in vitro against HEK-293 cells. Simulation study of best inhibitor revealed the specificity for the target protein. Hence, the compounds possessed the immense probability of being inhibitors of Pf pmt and may be optimized as antimalarial agent for combinational therapy to overcome the multidrug resistance and may also be used as template for optimization and rational drug designing.

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“…For orthosteric WNK inhibitors, this appears to be a limiting factor that cannot be overcome, since the ATP binding site of WNK kinases is highly conserved [69]. However, recent chemoinformatic analysis has revealed that structural specificities among the WNK isoforms do exist, particularly in the allosteric binding sites [78]. The exploitation of these structural differences may be an effective strategy for the development of specific WNK kinase inhibitors and certainly merits further investigation.…”

Section: Orthosteric Wnk Kinase Inhibitorsmentioning

confidence: 99%

WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension

Brown

Azlan

et al. 2020

Acta Pharmacol Sin

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Hypertension is the most prevalent health condition worldwide, affecting ~1 billion people. Gordon's syndrome is a form of secondary hypertension that can arise due to a number of possible mutations in key genes that encode proteins in a pathway containing the With No Lysine [K] (WNK) and its downstream target kinases, SPS/Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress responsive kinase 1 (OSR1). This pathway regulates the activity of the thiazide-sensitive sodium chloride cotransporter (NCC), which is responsible for NaCl reabsorption in the distal nephron. Therefore, mutations in genes encoding proteins that regulate the NCC proteins disrupt ion homeostasis and cause hypertension by increasing NaCl reabsorption. Thiazide diuretics are currently the main treatment option for Gordon's syndrome. However, they have a number of side effects, and chronic usage can lead to compensatory adaptations in the nephron that counteract their action. Therefore, recent research has focused on developing novel inhibitory molecules that inhibit components of the WNK-SPAK/OSR1-NCC pathway, thereby reducing NaCl reabsorption and restoring normal blood pressure. In this review we provide an overview of the currently reported molecular inhibitors of the WNK-SPAK/OSR1-NCC pathway and discuss their potential as treatment options for Gordon's syndrome.

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Cheminformatics Analysis of Dynamic WNK‐Inhibitor Interactions

Cited by 8 publications

References 46 publications

Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations

Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations

Docking predictions based Plasmodium falciparum phosphoethanolamine methyl transferase inhibitor identification and in-vitro antimalarial activity analysis

WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension

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