Tripathi Ashutosh, Bankaitis Vytas A
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Sciences Center, College Station, Texas, USA.
Department of Biochemistry and Biophysics, A&M Health Sciences Center, Texas, USA.
J Mol Med Clin Appl. 2017;2(1). doi: 10.16966/2575-0305.106. Epub 2017 Feb 10.
Accurate modeling of protein ligand binding is an important step in structure-based drug design, is a useful starting point for finding new lead compounds or drug candidates. The 'Lock and Key' concept of protein-ligand binding has dominated descriptions of these interactions, and has been effectively translated to computational molecular docking approaches. In turn, molecular docking can reveal key elements in protein-ligand interactions-thereby enabling design of potent small molecule inhibitors directed against specific targets. However, accurate predictions of binding pose and energetic remain challenging problems. The last decade has witnessed more sophisticated molecular docking approaches to modeling protein-ligand binding and energetics. However, the complexities that confront accurate modeling of binding phenomena remain formidable. Subtle recognition and discrimination patterns governed by three-dimensional features and microenvironments of the active site play vital roles in consolidating the key intermolecular interactions that mediates ligand binding. Herein, we briefly review contemporary approaches and suggest that future approaches treat protein-ligand docking problems in the context of a 'combination lock' system.
蛋白质配体结合的精确建模是基于结构的药物设计中的重要一步，是寻找新的先导化合物或药物候选物的有用起点。蛋白质 - 配体结合的“锁钥”概念主导了对这些相互作用的描述，并已有效地转化为计算分子对接方法。反过来，分子对接可以揭示蛋白质 - 配体相互作用中的关键要素，从而能够设计针对特定靶点的强效小分子抑制剂。然而，结合构象和能量的准确预测仍然是具有挑战性的问题。过去十年见证了更复杂的分子对接方法用于模拟蛋白质 - 配体结合和能量学。然而，准确建模结合现象所面临的复杂性仍然巨大。由活性位点的三维特征和微环境所支配的微妙识别和区分模式在巩固介导配体结合的关键分子间相互作用中起着至关重要的作用。在此，我们简要回顾当代方法，并建议未来的方法在“密码锁”系统的背景下处理蛋白质 - 配体对接问题。
