<i>In-silico</i> evaluations of the isolated phytosterols from <i>polygonum hydropiper</i> L against BACE1 and MAO drug targets

Ayaz, Muhammad; Wadood, Abdul; Sadiq, Abdul; Ullah, Farhat; Anichkina, Olga; Ghufran, Mehreen

doi:10.1080/07391102.2021.1940286

Cited by 18 publications

(12 citation statements)

References 25 publications

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“…As compared to apo‐BACE1, the average RMSD of the BACE1‐ L5 complex fluctuates at a significantly lower value during simulation (Figure 3a). The average RMSD of the BACE1‐ L5 complex was noted to be 0.23 nm, which matches the average RMSD value of 0.23 nm for the BACE1‐beta‐sitosterol complex (Figure S3) [35] . Further, RMSD was evaluated for the binding site of BACE1 in the absence and presence of L5 .…”

Section: Resultssupporting

confidence: 65%

“…ChemistrySelect complex was noted to be 0.23 nm, which matches the average RMSD value of 0.23 nm for the BACE1-beta-sitosterol complex (Figure S3). [35] Further, RMSD was evaluated for the binding site of BACE1 in the absence and presence of L5. The RMSD analysis of the binding site of BACE1 indicated higher stability of BACE1-L5 complex as compared to apo-BACE1 (Figure 3b).…”

Section: Systemmentioning

confidence: 99%

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Deciphering the Molecular Mechanism of Inhibition of β‐Secretase (BACE1) Activity by a 2‐Amino‐imidazol‐4‐one Derivative

Kaur

Goyal

2022

ChemistrySelect

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The β‐site amyloid precursor protein‐cleaving enzyme 1 (β‐secretase, BACE1) is a prominent drug target amongst all other targets of Alzheimer's disease (AD) as it is involved in the rate‐determining step of amyloid‐β (Aβ) production. Fan et al. identified 2‐amino‐imidazol‐4‐one derivative L5 as a potent inhibitor of BACE1 (IC50=0.12 μM, logP=2.49). However, it remains unclear how L5 inhibits the BACE1 activity. In this work, atomistic molecular dynamics (MD) simulations have been carried out to explore the interaction mechanism of L5 with BACE1. The molecular docking analysis highlighted strong binding (−9.1 kcal/mol) of L5 with the active site residues of BACE1. MD simulations revealed hydrogen bonds and hydrophobic contacts of L5 with the BACE1 active pocket residues control the dynamics of the flap and assist to attain the closed (non‐active) conformation. The binding free energy analysis depicted strong interaction of L5 with BACE1 (▵Gbinding=−34.6±3.6 kcal/mol) and highlighted the significant contribution of the active pockets, aspartic dyad, and flap residues of BACE1 in the binding with L5. The free energy landscape (FEL) analysis highlighted a close flap conformation in the lowest energy conformation of BACE1‐L5 complex as compared to open flap (active) conformation in apo‐BACE1. The study reveals the interaction mechanism of L5 with BACE1, which will be helpful for the structure‐based design of potent inhibitors against BACE1.

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Section: Resultssupporting

confidence: 65%

Section: Systemmentioning

confidence: 99%

Deciphering the Molecular Mechanism of Inhibition of β‐Secretase (BACE1) Activity by a 2‐Amino‐imidazol‐4‐one Derivative

Kaur

Goyal

2022

ChemistrySelect

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“…The identified compounds were docked for their binding capacity in the enzymes protein pocket via MOE-Dock tool in molecular operating environment (MOE) ( http://www.chemcomp.com ) [ 36 , 37 ]. Due to unavailability of α -glucosidase crystal structure, a previously reported homology model was used [ 38 ], whereas the α -amylase (4W93) 3D crystal structure was obtained from the Protein Databank (PDB).…”

Section: Methodsmentioning

confidence: 99%

Phytochemical Analysis, α-Glucosidase and Amylase Inhibitory, and Molecular Docking Studies on Persicaria hydropiper L. Leaves Essential Oils

Mahnashi

Alqahtani

Alyami

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. Medicinal plants and essentials oils are well known for diverse biological activities including antidiabetic potential. This study was designed to isolate essential oils from the leaves of Persicaria hydropiper L. (P. hydropiper), perform its phytochemical analysis, and explore its in vitro antidiabetic effects. Materials and Methods. P. hydropiper leaves essential oils (Ph.Los) were extracted using a hydrodistillation apparatus and were subjected to phytochemical analysis using the gas chromatography mass spectrometry (GC-MS) technique. Ph.Lo was tested against two vital enzymes including α-glucosidase and α-amylase which are important targets in type-2 diabetes. The identified compounds were tested using in silico approaches for their binding affinities against the enzyme targets using MOE-Dock software. Results. GC-MS analysis revealed the presence of 141 compounds among which dihydro-alpha-ionone, cis-geranylacetone, α-bulnesene, nerolidol, β-caryophyllene epoxide, and decahydronaphthalene were the most abundant compounds. Ph.Lo exhibited considerable inhibitory potential against α-glucosidase enzyme with 70% inhibition at 1000 μg mL−1 which was the highest tested concentration. The inhibitory activity of positive control acarbose was 77.30 ± 0.61% at the same tested concentration. Ph.Lo and acarbose exhibited IC50 of 170 and 18 µg mL−1 correspondingly. Furthermore, dose-dependent inhibitions were observed for Ph.Lo against α-amylase enzyme with an IC50 of 890 μg mL−1. The top-ranked docking conformation was observed for β-caryophyllene epoxide with a docking score of -8.3182 against α-glucosidase, and it has established seven hydrogen bonds and one H-pi interaction at the active site residues (Phe 177, Glu 276, Arg 312, Asp 349, Gln 350, Asp 408, and Arg 439). Majority of the identified compounds fit well in the binding pocket of Tyr 62, Asp 197, Glu 233, Asp 300, His 305, and Ala 307 active residues of α-amylase. β-Caryophyllene epoxide was found to be the most active inhibitor with a docking score of -8.3050 and formed five hydrogen bonds at the active site residues of α-amylase. Asp 197, Glu 233, and Asp 300 active residues were observed to be making polar interactions with the ligand. Conclusions. The current study revealed that Ph.Lo is rich in bioactive metabolites which might contribute to its enzyme inhibitory potential. Inhibition of these enzymes is the key target in reducing postprandial hyperglycemia. However, further detailed in vivo studies are required for their biological and therapeutic activities.

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“…As a result, the locus coeruleus, a brain's primary noradrenergic center with considerable distribution in the cortical regions, shows severe deterioration in AD. In AD, tyrosine hydroxylase (a flow-restricting protein for noradrenaline and dopamine production) and dopamine-beta-hydroxylase (DBH, the enzyme essential for noradrenaline generation) levels are also diminished (Ayaz et al, 2021). Furthermore, AD is linked to a FIGURE 3 A model of retinoic acid signaling in the central nervous system, which plays an important role in the stimulation of transcriptional machinery to modulate the cholinergic neurotransmission through the production of choline-acetyl transferase mRNA and acetylcholine on the interaction of retinoic acid with its nuclear receptors.…”

Section: Retinoids Mediated Neurotransmission In Alzheimer's Diseasementioning

confidence: 99%

“…As a result, the locus coeruleus, a brain’s primary noradrenergic center with considerable distribution in the cortical regions, shows severe deterioration in AD. In AD, tyrosine hydroxylase (a flow-restricting protein for noradrenaline and dopamine production) and dopamine-beta-hydroxylase (DBH, the enzyme essential for noradrenaline generation) levels are also diminished ( Ayaz et al, 2021 ). Furthermore, AD is linked to a lower extent of norepinephrine in the cortex ( Mann et al, 1980 ), and dopamine in the cortex, striatum, and amygdala ( Iversen et al, 1983 ).…”

Section: Retinoids Mediated Neurotransmission In Alzheimer’s Diseasementioning

confidence: 99%

Therapeutic insights elaborating the potential of retinoids in Alzheimer’s disease

et al. 2022

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Alzheimer’s disease (AD) is perceived with various pathophysiological characteristics such oxidative stress, senile plaques, neuroinflammation, altered neurotransmission immunological changes, neurodegenerative pathways, and age-linked alterations. A great deal of studies even now are carried out for comprehensive understanding of pathological processes of AD, though many agents are in clinical trials for the treatment of AD. Retinoids and retinoic acid receptors (RARs) are pertinent to such attributes of the disease. Retinoids support the proper functioning of the immunological pathways, and are very potent immunomodulators. The nervous system relies heavily on retinoic acid signaling. The disruption of retinoid signaling relates to several pathogenic mechanisms in the normal brain. Retinoids play critical functions in the neuronal organization, differentiation, and axonal growth in the normal functioning of the brain. Disturbed retinoic acid signaling causes inflammatory responses, mitochondrial impairment, oxidative stress, and neurodegeneration, leading to Alzheimer’s disease (AD) progression. Retinoids interfere with the production and release of neuroinflammatory chemokines and cytokines which are located to be activated in the pathogenesis of AD. Also, stimulating nuclear retinoid receptors reduces amyloid aggregation, lowers neurodegeneration, and thus restricts Alzheimer’s disease progression in preclinical studies. We outlined the physiology of retinoids in this review, focusing on their possible neuroprotective actions, which will aid in elucidating the critical function of such receptors in AD pathogenesis.

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In-silico evaluations of the isolated phytosterols from polygonum hydropiper L against BACE1 and MAO drug targets

Cited by 18 publications

References 25 publications

Deciphering the Molecular Mechanism of Inhibition of β‐Secretase (BACE1) Activity by a 2‐Amino‐imidazol‐4‐one Derivative

Deciphering the Molecular Mechanism of Inhibition of β‐Secretase (BACE1) Activity by a 2‐Amino‐imidazol‐4‐one Derivative

Phytochemical Analysis, α-Glucosidase and Amylase Inhibitory, and Molecular Docking Studies on Persicaria hydropiper L. Leaves Essential Oils

Therapeutic insights elaborating the potential of retinoids in Alzheimer’s disease

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