In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures.
Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA) make it as a good candidate for designing and development of the new anticonvulsant medications.



Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection of the screened compounds to mice.



Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tert-Butylcyclo-hexanecarboxylic acid showed significant activity with ED50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM.



Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA.
Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran.
Ali
A
Gharibi Loron
Drug Design and Bioinformatics Unit, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
Soroush
S
Sardari
Department of Pharmacology and Biochemistry, School of Medicine, Shahed University, Tehran, Iran.
Jamshid
J
Narenjkar
Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran.
Mohammad
M
Sayyah
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D015195:Drug Design; D004597:Electroshock / Q000009:adverse effects; D004827:Epilepsy / Q000188:drug therapy; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000633:toxicity; D010648:Phenylacetates / Q000627:therapeutic use; D010654:Phenylbutyrates / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D012765:Shikimic Acid / Q000627:therapeutic use
D000927:Anticonvulsants; D010648:Phenylacetates; D010654:Phenylbutyrates; D004281:Docosahexaenoic Acids; D012765:Shikimic Acid; C075773:4-phenylbutyric acid; C025136:phenylacetic acid; C039714:2-phenylbutyric acid; D010433:Pentylenetetrazole
Drug screening; Epilepsy; Maximal electroshock; Pentylenetetrazole