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Viscosine as a Potent and Safe Antipyretic Agent Evaluated by Yeast-Induced Pyrexia Model and Molecular Docking Studies.

ABSTRACT: The antipyretic potential of viscosine, a natural product isolated from the medicinal plant Dodonaea viscosa, was investigated using yeast-induced pyrexia rat model, and its structure-activity relationship was investigated through molecular docking analyses with the target enzymes cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1). The in vivo antipyretic experiments showed a progressive dose-dependent reduction in body temperatures of the hyperthermic test animals when injected with viscosine. Comparison of docking analyses with target enzymes showed strongest bonding interactions (binding energy -17.34 kcal/mol) of viscosine with the active-site pocket of mPGES-1. These findings suggest that viscosine shows antipyretic properties by reducing the concentration of prostaglandin E2 in brain through its mPGES-1 inhibitory action and make it a potential lead compound for developing effective and safer antipyretic drugs for treating fever and related pathological conditions.

SUBMITTER: Muhammad A

PROVIDER: S-EPMC6732982 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Viscosine as a Potent and Safe Antipyretic Agent Evaluated by Yeast-Induced Pyrexia Model and Molecular Docking Studies.

Muhammad Akhtar A Khan Behramand B Iqbal Zafar Z Khan Amir Zada AZ Khan Inamullah I Khan Kashif K Alamzeb Muhammad M Ahmad Nasir N Khan Khalid K Lal Badshah Syed S Ullah Asad A Muhammad Sayyar S Jan Muhammad Tariq MT Nadeem Said S Kabir Nurul N

ACS omega 20190821 10

The antipyretic potential of viscosine, a natural product isolated from the medicinal plant <i>Dodonaea viscosa</i>, was investigated using yeast-induced pyrexia rat model, and its structure-activity relationship was investigated through molecular docking analyses with the target enzymes cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1). The in vivo antipyretic experiments showed a progressive dose-dependent reduction in body temperatures of ...[more]

PMID: 31508540

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Project description:IntroductionThe current study was designed to synthesize derivatives of succinimide and compare their biological potency in anticholinesterase, alpha-glucosidase inhibition, and antioxidant assays.MethodsIn this research, two succinimide derivatives including (S)-1-(2,5-dioxo-1-phenylpyrrolidin-3-yl) cyclohexanecarbaldehyde (Compound 1) and (R)-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-phenylpropanal (Compound 2) were synthesized using Michael addition. Both the compounds, ie, 1 and 2 were evaluated for in-vitro acetylcholinesterase (AChE), butyrylctcholinesterase (BChE), antioxidant, and α-glucosidase inhibitory potentials. Furthermore, molecular docking was performed using Molecular Operating Environment (MOE) to explore the binding mode of both the compounds against different enzymes. Lineweaver-Burk plots of enzyme inhibitions representing the reciprocal of initial enzyme velocity versus the reciprocal of substrate concentration in the presence of synthesized compounds and standard drugs were constructed using Michaelis-Menten kinetics.ResultsIn AChE inhibitory assay, compounds 1 and 2 exhibited IC50 of 343.45 and 422.98 µM, respectively, against AChE enzyme. Similarly, both the compounds showed IC50 of 276.86 and 357.91 µM, respectively, against BChE enzyme. Compounds 1 and 2 displayed IC50 of 157.71 and 471.79 µM against α-glucosidase enzyme, respectively. In a similar pattern, compound 1 exhibited to be more potent as compared to compound 2 in all the three antioxidant assays. Compound 1 exhibited IC50 values of 297.98, 332.94, and 825.92 µM against DPPH, ABTS, and H2O2 free radicals, respectively. Molecular docking showed a triple fold in the AChE and BChE activity for compound 1 compared with compound 2. The compound 1 revealed good interaction against both the AChE and BChE enzymes which revealed the high potency of this compound compared to compound 2.ConclusionBoth succinimide derivatives exhibited considerable inhibitory activities against cholinesterases and α-glucosidase enzymes. Of these two, compound 1 revealed to be more potent against all the in-vitro targets which was supported by molecular docking with the lowest binding energies. Moreover, compound 1 also proved to have antiradical properties.

Project description:BackgroundBeta-site amyloid precursor protein cleaving enzyme (BACE-1) is a single-membrane protein belongs to the aspartyl protease class of catabolic enzymes. This enzyme involved in the processing of the amyloid precursor protein (APP). The cleavage of APP by BACE-1 is the rate-limiting step in the amyloid cascade leading to the production of two peptide fragments Aβ40 and Aβ42. Among two peptide fragments Aβ42 is the primary species thought to be responsible for the neurotoxicity and amyloid plaque formation that lead to memory and cognitive defects in Alzheimer's disease (AD). AD is a ravaging neurodegenerative disorder for which no disease-modifying treatment is currently available. Inhibition of BACE-1 is expected to stop amyloid plaque formation and emerged as an interesting and attractive therapeutic target for AD.MethodsLigand-based computational approach was used to identify the molecular chemical features required for the inhibition of BACE-1 enzyme. A training set of 20 compounds with known experimental activity was used to generate pharmacophore hypotheses using 3D QSAR Pharmacophore Generation module available in Discovery studio. The hypothesis was validated by four different methods and the best hypothesis was utilized in database screening of four chemical databases like Maybridge, Chembridge, NCI and Asinex. The retrieved hit compounds were subjected to molecular docking study using GOLD 4.1 program.ResultsAmong ten generated pharmacophore hypotheses, Hypo 1 was chosen as best pharmacophore hypothesis. Hypo 1 consists of one hydrogen bond donor, one positive ionizable, one ring aromatic and two hydrophobic features with high correlation coefficient of 0.977, highest cost difference of 121.98 bits and lowest RMSD value of 0.804. Hypo 1 was validated using Fischer randomization method, test set with a correlation coefficient of 0.917, leave-one-out method and decoy set with a goodness of hit score of 0.76. The validated Hypo 1 was used as a 3D query in database screening and retrieved 773 compounds with the estimated activity value <100 nM. These hits were docked into the active site of BACE-1 and further refined based on molecular interactions with the essential amino acids and good GOLD fitness score.ConclusionThe best pharmacophore hypothesis, Hypo 1, with high predictive ability contains chemical features required for the effective inhibition of BACE-1. Using Hypo 1, we have identified two compounds with diverse chemical scaffolds as potential virtual leads which, as such or upon further optimization, can be used in the designing of new BACE-1 inhibitors.

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Viscosine as a Potent and Safe Antipyretic Agent Evaluated by Yeast-Induced Pyrexia Model and Molecular Docking Studies.

Publications

Viscosine as a Potent and Safe Antipyretic Agent Evaluated by Yeast-Induced Pyrexia Model and Molecular Docking Studies.

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