Ligand based drug design of new heterocyclic imines of GABA analogues: A molecular docking approach for the discovery of new GABA-AT inhibitors.

Bijo Mathew, Githa Elizabeth Mathew, Jerad Suresh, Dhasthakeer Usman, Puthucode Natarajan Shiva Subramanyan, Kallivalappil Fathima Safna
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Abstract

Background: 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.

Experimental design: 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.

Results: 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.

Conclusion: 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.

基于配体的 GABA 类似物新杂环亚胺药物设计:发现新 GABA-AT 抑制剂的分子对接方法。
背景:抑制性神经递质γ-氨基丁酸(GABA)的降解主要由GABA氨基转移酶(GABA-AT)催化,其活性过高会导致抽搐。抑制 GABA-AT 可增加 GABA 的浓度,从而终止抽搐。多项研究表明,GABA 类似物可能是设计 GABA-AT 强效抑制剂的理想支架。GABA 类似物通过血脑屏障(BBB)的能力较差,因此治疗指数一直较低。然而,基于机制的 GABA-AT 抑制剂 Vigabatrin 目前已被批准用于治疗癫痫,但它具有有害的副作用,因此需要改进 GABA-AT 灭活剂:实验设计:在我们目前的硅学研究中,我们采用了基于拉马克遗传算法的 AutoDock 4.2 对包含 35 个条目(GABA 的希夫碱)的化合物库进行虚拟筛选,以寻找新型的 GABA-AT 选择性抑制剂:结果:通过灵活的分子对接,我们提出这些设计的分子可以成功地结合到 GABA-AT 的活性口袋中,与标准的维加巴曲林相比具有良好的预测亲和力。在所设计的类似物中,HIG18、HIG28和HIG30的结合自由能分别为-10.25、-9.88和-9.31 kcal/mol,预测抑制常数分别为0.03、0.05和0.15 µM:通过基于配体的药物设计,我们提出 GABA 的取电子苯基取代杂环亚胺可作为合成和测试该类新 GABA-AT 抑制剂的理想结构。我们假设,与杂环系统结合在一起的偶氮甲基连接的新型 GABA 类似物可以增加亲和力和亲油性,从而有可能在治疗惊厥方面产生较小的毒性作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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