Central nervous system agents in medicinal chemistry最新文献

{"title":"Ligand based drug design of new heterocyclic imines of GABA analogues: A molecular docking approach for the discovery of new GABA-AT inhibitors.","authors":"Bijo Mathew, Githa Elizabeth Mathew, Jerad Suresh, Dhasthakeer Usman, Puthucode Natarajan Shiva Subramanyan, Kallivalappil Fathima Safna","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>Degradation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) is mainly catalysed by GABA aminotransferase (GABA-AT), excessive activity of which leads to convulsions. Inhibition of GABA-AT increases the concentration of GABA and can terminate the convulsions. Several studies have revealed that GABA analogues could be the outstanding scaffolds for the design of potent inhibitors of GABA-AT. The poor ability of GABA analogues to cross the blood-brain barrier (BBB), always produces low therapeutic index. However, Vigabatrin, a mechanism-based inhibitor of GABA-AT, is currently approved treatment of epilepsy, but it has harmful side effects, leaving a need for improved GABA-AT inactivators.</p><p><strong>Experimental design: </strong>In our present in silico investigation, AutoDock 4.2,-based on Lamarckian genetic algorithm was employed for virtual screen of a compound library with 35 entries (Schiff's bases of GABA) in search for novel and selective inhibitors of GABA-AT.</p><p><strong>Results: </strong>By means of flexible type of molecular docking, we proposed that these designed molecules could successfully bind into the active pocket of GABA-AT with good predicted affinities in comparison to standard vigabatrin. Among the designed analogues, HIG18, HIG28 and HIG30 showed significant binding free energy of -10.25, -9.88 and -9.31 kcal/mol with predicted inhibitory constant values of 0.03, 0.05 and 0.15 µM respectively.</p><p><strong>Conclusion: </strong>Using ligand-based drug design, we proposed that electron withdrawing phenyl substituted heterocyclic imines of GABA could be considered as promising structures for synthesis and testing of new GABA-AT inhibitors from this class. We hypothesize that novel GABA analogues with an azomethine linkage incorporated with heterocyclic system can have increased affinity and more lipophilic character that would provide a probability of having less toxic effect in the therapy of convulsions.</p>","PeriodicalId":93930,"journal":{"name":"Central nervous system agents in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}