Structure–activity relationship of phenytoinergic antiepileptic drugs related to ameltolide (original) (raw)
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The Structure-Activity Relatıonships of Familiar Antiepileptic Drugs and Na+ Channels
Hittite Journal of Science and Engineering
The aim of this study is to examine the effects of drug active compounds, which are widely used in the treatment of epilepsy, on voltage-gated Na+ channels are important channels that advance the action potential in the excitation direction by molecular docking method. These molecules have been selected considering the physiopathological effect mechanisms of epilepsy disease. When the action potential is stimulated, Na+ channels allow sodium ion entry into the cell and cause epilepsy seizures. For this reason, PDB ID: 4PA6 receptor, which acts as an antagonist according to its activity on the canal in the formation of epileptic seizures, was chosen for molecular docking study. As a result of molecular docking studies; Phenytoin gave the best binding affinity for 4PA6 with a value of -7.7 kcal/mol. Other results in descending order (as kcal/mol); Mesuximide (-7.5), Remasemide (-7.3), Tiagabine (-7.1), Ethotoin and Mephenytoin (-7.0), Primidon (-6.9), Topiramate (-6.6), Oxcarbazepine ...
Epilepsy is a common brain disease that is characterized by recurrent and spontaneous seizures that result from abnormal and excessive synchronization of neuronal activity. Whereas, accumulation of Ca++ in presynaptic terminals, leading to improved neurotransmitter release. In additional, depolarization-induced inauguration of the NMDA subtype of the excitatory amino acid receptor, which causes more Ca++ influx and neuronal activation. The main aim of this study to focus on the deactivation of Ca++ influx and prevent the augmentation of neuron activation. However, we performed molecular modeling of novel 1,3,4-thiadiazole derivatives keeping in view structural requirement of pharmacophore and Quantitative structure activity relationship (QSAR) and evaluated in silico anticonvulsant activity. Docking procedures allow virtually screening a database of compounds and predict the strongest binder based on various scoring functions. In the docking study, targeted ligand produced significantly affinity with the calcium channel receptor which is slightly higher than the phenytoin drug. A computational study was also carried out including prediction of pharmacokinetic properties, toxicity and bioactivity studies. All above parameter was calculated which exhibited slightly excellent compared than standard Phenytoin drug. The above observation suggested that these compounds would serve as better lead for anticonvulsant screening for future drug design perspective.
Ligand based pharmacophore model development for the identification of novel antiepileptic compound
Epilepsy Research, 2012
Epilepsy is a common neurological disorder throughout the world which is characterized by recurrent unprovoked epileptic seizures. A need exists for the development of new antiseizure drugs with improved efficacy and tolerability, as several of the currently available antiepileptic drugs (AEDs) have been associated with severe side effects. A ligand based pharmacophore approach has been generated for 44 new antiepileptic compounds with emphasis on the development of new drugs by using LigandScout software and distance estimation using Jmol. The pharmacophore of the compounds contained three features hydrophobic unit, hydrogen bonding domain and electron donor. The pharmacophore models derived were then filtered using the Lipinski's rule of five criteria and orally bio-available compounds were obtained. Thus, this approach was able to reclaim few leads which had projected inhibitory activity alike to most active compounds with suitable calculated drug-like properties and therefore they could be recommended for further studies.
Journal of Crystallographic and Spectroscopic Research, 1986
The crystal structures of endo-and exo-2, 3-dimethoxy-N-[8(phenylmethyl)-8azabicyclo[3.2.1]oct-2-yl]benzamide hydrochloride have been determined by single-crystal X-ray diffraction techniques, and refined by full-matrix least squares. The endo-compound crystallizes in the monoclinic space group P21/n with a = 12.389(2) ,~, b = 22.861(3) A, c = 8.019(2) A,/3 = 93.58(2) ~ and Z = 4; the exo-compound crystallizes in the monoclinic space group P21/ a with a = 26.295(12) A, b = 12.503(4) A, c = 6.667(7) .&,/3 = 97.80(6) ~ and Z = 4. The calculated densities are 1.22 and 1.27 gcm -3 respectively. Final R-factors are 0.04 for the endo and 0.05 for the exo-compound. Comparison with a very active analog, the tropapride, suggests that the lack of antipsychotic activity is due to a different orientation of the dimethoxyphenyl or carbonyl group for the exo-and endo-compound, respectively.
An ab initio study of anticonvulsants
Journal of Molecular Structure-theochem, 1994
A systematic theoretical study of anticonvulsant compounds has been performed for the first time, utilizing ab initio molecular orbital techniques. The geometry and pharmacophore charge distribution, the effect of substituents and protonation of the imide nitrogen on the pharmacophore ring charge distribution and drug-receptor interactions have been studied in detail. The results indicate a rigid, typical and highly charged environment on the pharmacophore ring which is not altered by substituents or protonation of the imide nitrogen. The intermolecular interaction calculations indicate that the drug is capable of disrupting normal hydrogen-bonding patterns in lipoproteins or phospholipids. The results also indicate common cellular ions as strong competitors for the binding site.
DFT studies on global parameters, antioxidant mechanism and molecular docking of amlodipine besylate
Computational Biology and Chemistry, 2019
Highlights: The detailed confab on the computational calculation on AMB revealed o Global descriptors revealed it is reactive o It has the ability to donate electrons easily o It shows better NLO activity o It can easily scavenge free radicals in biological system o It reduces the oxidative stress in living system and reduces the hypertension ABSTRACT Amlodipine besylate (AMB) is a synthetic dihydropyridine calcium channel blocker with antihypertensive and anti-anginal effects. Quantum computational investigations on AMB were done using DFT/B3LYP/6-311++G (d, p) level of theory, to study the molecular structural properties, nonlinear properties and antioxidant properties of AMB. The electrophilic and nucleophilic sites along with complete NBO analysis helps to locate the intermolecular electronic interactions and their stabilization energies. Complete NBO analysis was additionally done to locate the intermolecular electronic interactions and their stabilization energies. Charge distributions of Mulliken population, NBO and MEP are correlated. Also, the antioxidant properties of AMB were assessed to check whether these antioxidant effects contribute to the effects of antioxidant therapy. Further, the molecular docking studies of these compounds demonstrated a good selectivity profile with Monoamine oxidase B with better binding affinity and confirms AMB is a potent antioxidant.
Sumathi Publications, 2019
Epilepsy is characterized by the presence of recurrent seizures. A seizure can be defined as “an episodic disturbance of movement, feeling, or consciousness caused by sudden synchronous, inappropriate, and excessive electrical discharges in the cerebral cortex”. One in every three patients with epilepsy is probable to be severely disabled. It is continuing this scenario as an attempt to develop potent and nontoxic anticonvulsant agents. Recently discovery of benzothiazepine derivatives as an anticonvulsant agent is significant area for research in medicinal chemistry as it is free from all side effects which is shown by a developed as an anticonvulsant agent. In this paper, we have presented results of 2D, and 3D docking poses studies of a series of 300 (Three series) molecules containing 1,5-benzothiazepine pharmacophore as anti-convulsant agents. Docking analysis was utilized to predict the mechanism of action of the designed derivatives for anticonvulsant potential. All the molecules exhibited binding score in the range of -82.61 to -118.25 kcal/mol. Most active molecules from Series 1, 2 and 3 exhibited hydrogen bond interactions with LEU282B, LEU282B and LEU282B. Also for the selected standard sodium phenytoin showed the hydrogen bond interaction with LYS637A. It was noted that the docking score of 1a to 10a, 101b to 110b and 201c to 210c was almost same as that of selected standard sodium phenytoin. Protein showed hydrogen bonding with all synthesized compound showed potential against the epilepsy with GABA nergic mechanism. Keywords: Anti-convulsant; 1,5-benzothiazepine; V-Life MDS 4.3
Pharmaceutical Sciences, 2020
Background: These days epilepsy is a common neurological disorder, which can affect on quality of life by unpredictable seizure. Thalidomide is one of the drugs to control the epilepsy but side effects such as teratogenicity, made it difficult to use. Methods: Six new analogues of N-aryl-4-(1,3-dioxoisoindolin-2-yl)benzamides were synthesized and tested for anti-seizure activity. To evaluate the anti-seizure activity of these new derivatives, 40 mice in 8 groups were received 10 mg/Kg of each new derivatives 30 min before the injection of pentylenetetrazole (PTZ, 70 mg/kg) to induced seizures. Latency time to first symptom of seizure was measured and compared to vehicle and standard groups. Docking methodology was applied to study on mode of interaction between GABAA receptor and synthetized compounds. Results: Structures of the all synthesized compounds were confirmed by NMR and mass spectroscopy. The latency time and mortality rate were individually measured for an hour after inje...
Computational studies on α-aminoacetamide derivatives with anticonvulsant activities
Beni-Suef University Journal of Basic and Applied Sciences, 2018
Computational methods were used to study the structural parameters that influence that anticonvulsant activity of some α-aminoacetamides which were active in maximal electroshock seizure test. Their molecular structures were optimized with B3LYP/631G** density function theory method using Spartan 14 software. Modified-Kmediod clustering algorithm was used for data division, genetic function algorithm was used for variable selection and multiple linear regressions method was used for model construction. Developed model was statistically significant with coefficient of determination (R 2) of 0.957, cross-validated R 2 i.e. Q 2 of 0.927, variance ratio (F 4,15) of 82.94, Y-randomization R 2 i.e. c R 2 P of 0.840 and predicted R 2 (R 2 Pred) of 0.812. The molecular descriptors contained in the model were GATS8c (Geary autocorrelation of lag-8/weighted by atomic charges); VCH-7 (valence chain of order 7); VE3_D (Logarithmic coefficient sum of the last eigenvector from topological distance matrix) and RDF100p (radial distribution function − 100/weighted by polarizability). Molecular docking result showed that studied compounds had high binding affinity for neuronal sodium channel (PDB: 2KaV). Their binding affinity compared favorably with that of phenytoin, a validated sodium channel blocker. In addition, a linear relationship existed between anticonvulsant activity of studied compounds and their binding affinity for neuronal sodium channel.