Indian Institute of Chemical Biology (A unit of CSIR), Structural Biology and Bioinformatics Division, 4, Raja S.C. Mullick Road, Kolkata-700032, India +91 33 2473 3491 ext. 854 ; +91 33 2473 5197 ;
Expert Opin Drug Discov. 2010 May;5(5):441-60. doi: 10.1517/17460441003789363.
GABA(A) ion channel is a validated drug target, implicated in the pathophysiology of various neurological and psychiatric disorders. Structural investigations on GABA(A) are currently precluded in the absence of experimentally resolved structure. Pharmacophore modeling circumvents such issues and proves to be a powerful and successful method in drug discovery.
The present reviews encompass pharmacophoric models available in the literature for the orthosteric GABA and the allosteric benzodiazepine binding site. Success stories from these simplistic pharmacophore models in scaffold hopping and strategic lead optimization have been highlighted. Recent advances in pharmacophore modeling that can leverage CNS drug discovery programs and deliver astounding results have been reviewed.
Readers are bound to gain a comprehensive insight on different computational techniques used by different groups to arrive at simple, yet sophisticated pharmacophore models. In the absence of experimentally unresolved active site geometry of GABA(A), these models will provide the reader an opportunity to translate these pharmacophoric features to the microscopic phenomenon of supramolecular ligand interaction.
Pharmacophore modeling has now evolved as a mainstay approach for lead generation and optimization in drug discovery programs. Of late, many advances in pharmacophore perception have emerged. Such advancements should be used to confront activity profiling and early stage risk assessment in a high-throughput fashion. Extending such technologies has the potential not only to reduce time and cost, but also to prevent late stage attrition in drug discovery.
GABA(A) 离子通道是一个经过验证的药物靶点，与各种神经和精神疾病的病理生理学有关。由于缺乏实验解决的结构，目前无法对 GABA(A) 进行结构研究。药效团建模规避了这些问题，并且被证明是药物发现中的一种强大而成功的方法。
本篇综述涵盖了文献中 GABA 的正构和苯二氮䓬结合位点的药效团模型。从这些简单的药效团模型在支架跳跃和策略性先导优化方面的成功案例中，突出了它们的作用。本文还回顾了药效团建模的最新进展，这些进展可以利用中枢神经系统药物发现计划并带来惊人的结果。
读者一定会全面了解不同研究小组用于得出简单而复杂的药效团模型的不同计算技术。在缺乏 GABA(A) 的实验未解决的活性位点几何形状的情况下，这些模型将为读者提供一个机会，将这些药效团特征转化为超分子配体相互作用的微观现象。
药效团建模现在已经成为药物发现计划中生成和优化先导化合物的主要方法。最近，药效团感知方面出现了许多进展。应该利用这些进展以高通量的方式进行活性分析和早期阶段风险评估。扩展这些技术不仅有可能缩短时间和降低成本，而且还有可能防止药物发现的后期淘汰。
