Azam Faizul, Abugrain Ismaiel Mohamed, Sanalla Mohamed Hussin, Elnaas Radwan Fatahalla, Rajab Ibrahim Abdassalam Ibn
Faculty of Pharmacy, Misurata University, PO Box 2873, Misurata, Libya.
Bioinformation. 2013 Oct 16;9(17):864-9. doi: 10.6026/97320630009864. eCollection 2013.
Glutamate receptors have been implicated in various neurological disorders and their antagonism offers a suitable approach for the treatment of such disorders. The field of drug design and discovery aims to find best medicines to prevent, treat and cure diseases quickly and efficiently. In this regard, computational tools have helped medicinal chemists modify and optimize molecules to potent drug candidates with better pharmacokinetic profiles, and guiding biologists and pharmacologists to explore new disease genes as well as novel drug targets. In the present study, to understand the structural requirements for AMPA receptor antagonism, molecular docking study was performed on 41 structurally diverse antagonists based on quinoxaline nucleus. Lamarckian genetic algorithm methodology was employed for docking simulations using AutoDock 4.2 program. The results obtained signify that the molecular docking approach is reliable and produces a good correlation coefficient (r(2) = 0.6) between experimental and docking predicted AMPA receptor antagonistic activity. The aromatic moiety of quinoxaline core has been proved to be vital for hydrophobic contacts exhibiting - interactions in docked conformations. However, polar moieties such as carboxylic group and 1,2,4-triazole moieties were noted to be sites for hydrophilic interactions in terms of hydrogen bonding with the receptor. These analyses can be exploited to design and develop novel AMPA receptor antagonists for the treatment of different neurological disorders.
谷氨酸受体与多种神经系统疾病有关，对其进行拮抗作用为治疗此类疾病提供了一种合适的方法。药物设计与发现领域旨在找到能快速有效地预防、治疗和治愈疾病的最佳药物。在这方面，计算工具帮助药物化学家将分子修饰和优化为具有更好药代动力学特征的有效候选药物，并指导生物学家和药理学家探索新的疾病基因以及新的药物靶点。在本研究中，为了解AMPA受体拮抗作用的结构要求，对基于喹喔啉核的41种结构多样的拮抗剂进行了分子对接研究。使用AutoDock 4.2程序，采用拉马克遗传算法方法进行对接模拟。所得结果表明，分子对接方法是可靠的，并且在实验和对接预测的AMPA受体拮抗活性之间产生了良好的相关系数（r(2) = 0.6）。喹喔啉核心的芳香部分已被证明对于在对接构象中表现出 - 相互作用的疏水接触至关重要。然而，就与受体形成氢键而言，极性部分如羧基和1,2,4 - 三唑部分被认为是亲水相互作用的位点。这些分析可用于设计和开发用于治疗不同神经系统疾病的新型AMPA受体拮抗剂。
