β-N-oxalyl-L-α, β- diaminopropionic acid induces HRE expression by inhibiting HIF-prolyl hydroxylase-2 in normoxic conditions

Eslavath, Ravi Kumar; Sharma, Deepak; Omar, Nabil A. M. Bin; Chikati, Rajasekhar; Teli, Mahesh Kumar; Rajanikant, G. K.; Singh, Surya S.

doi:10.1016/j.ejphar.2016.07.007

Cited by 8 publications

(3 citation statements)

References 54 publications

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“…All water molecules and the extra chains (except A) were removed from the complex followed by minimization using the OPLS3e force field. Further, H‐atoms were added to the protein to correct ionization and tautomeric states of amino acid residues 20,21 …”

Section: Methodsmentioning

confidence: 99%

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In silico identification of prolyl hydroxylase inhibitor by per‐residue energy decomposition‐based pharmacophore approach

Teli

Kumar

Yadav

et al. 2021

J of Cellular Biochemistry

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Hypoxia is an effective preconditioning stimulus and many cellular responses to hypoxia are mediated through a transcription control complex termed the hypoxia‐inducible factor (HIF). The stability and activation of HIF are governed by HIF prolyl‐4‐hydroxylases 2 (PHD2). Hence, the development of a small molecule inhibitor for prolyl hydroxylase has been suggested as a potentially useful therapeutic strategy for the treatment of oxidative/ischemic stress conditions. Thus, to unveil a novel human PHD2 inhibitor, a custom‐based virtual screening was carried out to identify the potential inhibitors against PHD2 based on; (1) the per‐residue energy decomposition (PRED)‐based pharmacophore model, (2) molecular docking, and (3) MD approaches. The PRED analysis was performed to identify the common interaction pattern of HIF fragment (5L9B) and crystallized ligand (4JZR) to develop a relevant accurate allosteric pharmacophore model. The custom pharmacophore model (AAARR) was developed and further used to screen multiple databases. The docking was performed as a secondary strategy for screening the pharmacophore hits. Furthermore, the docked complexes were screened by molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM–GBSA) based binding free energy calculations to determine the binding energy of the inhibitors and to identify crucial interaction energy fingerprint. One hit has demonstrated good binding free energy and a better binding affinity for PHD2 compared to the other four selected ligands. Thus, the results obtained from pharmacophore, docking, and MD simulations depicted that linker length and metal binding in the scaffold could be effectively used as a potent inhibitor toward human PHD2 in AD therapeutics.

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Section: Methodsmentioning

confidence: 99%

“…Further, H-atoms were added to the protein to correct ionization and tautomeric states of amino acid residues. 20,21…”

Section: Protein Preparationmentioning

confidence: 99%

In silico identification of prolyl hydroxylase inhibitor by per‐residue energy decomposition‐based pharmacophore approach

Teli

Kumar

Yadav

et al. 2021

J of Cellular Biochemistry

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“…Low levels of ROS can act as second messengers and are also known to alter the function of the transcription factor HIF-1 ( 47 ). Since L-ODAP activates protein kinase C ( 26 ) and stabilizes HIF ( 48 ), which is known to mediate angiogenesis, invasion, and cell survival ( 49 ), this study further opens up avenues to explore the beneficial effects of this amino acid as an initiator of ROS- and HIF-1-mediated signaling cascades.…”

Section: Discussionmentioning

confidence: 97%

Proteomic Changes in Chick Brain Proteome Post Treatment with Lathyrus Sativus Neurotoxin, β-N-Oxalyl-L-α,β-Diaminopropionic Acid (L-ODAP): A Better Insight to Transient Neurolathyrism

et al. 2018

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Neurolathyrism is a neurodegenerative disorder characterized by spastic paraplegia resulting from the excessive consumption of Lathyrus sativus (Grass pea). β-N-Oxalyl-L-α,β-diaminopropionic acid (L-ODAP) is the primary neurotoxic component in this pea. The present study attempted to evaluate the proteome-wide alterations in chick brain 2 hr and 4 hr post L-ODAP treatment. Proteomic analysis of chick brain homogenates revealed several proteins involved in cytoskeletal structure, signaling, cellular metabolism, free radical scavenging, oxidative stress and neurodegenerative disorders were initially up-regulated at 2 hr and later recovered to normal levels by 4 hr. Since L-ODAP mediated neurotoxicity is mainly by excitotoxicity and oxidative stress related dysfunctions, this study further evaluated the role of L-ODAP in apoptosis in vitro using human neuroblastoma cell line, IMR-32. The in vitro studies carried out at 200 μM L-ODAP for 4 hr indicate minimal intracellular ROS generation and alteration of mitochondrial membrane potential though not leading to apoptotic cell death. L-ODAP at low concentrations can be explored as a stimulator of various reactive oxygen species (ROS) mediated cell signaling pathways not detrimental to cells. Insights from our study may provide a platform to explore the beneficial side of L-ODAP at lower concentrations. This study is of significance especially in view of the Government of India lifting the ban on cultivation of low toxin Lathyrus varieties and consumption of this lentil.

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Grass Pea: Remodeling an Ancient Insurance Crop for Climate Resilience

Sarkar

Emmrich

Sarker

et al. 2019

Genomic Designing of Climate-Smart Pulse Crops

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β-N-oxalyl-L-α, β- diaminopropionic acid induces HRE expression by inhibiting HIF-prolyl hydroxylase-2 in normoxic conditions

Cited by 8 publications

References 54 publications

In silico identification of prolyl hydroxylase inhibitor by per‐residue energy decomposition‐based pharmacophore approach

In silico identification of prolyl hydroxylase inhibitor by per‐residue energy decomposition‐based pharmacophore approach

Proteomic Changes in Chick Brain Proteome Post Treatment with Lathyrus Sativus Neurotoxin, β-N-Oxalyl-L-α,β-Diaminopropionic Acid (L-ODAP): A Better Insight to Transient Neurolathyrism

Grass Pea: Remodeling an Ancient Insurance Crop for Climate Resilience

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