Institute of Pharmacy and Food Chemistry, University of Würzburg, 97074, Würzburg, Germany.
J Comput Aided Mol Des. 2011 Nov;25(11):1053-69. doi: 10.1007/s10822-011-9483-4. Epub 2011 Nov 11.
Inhibition of the production of fatty acids as essential components of the mycobacterial cell wall has been an established way of fighting tuberculosis for decades. However, increasing resistances and an outdated medical treatment call for the validation of new targets involved in this crucial pathway. In this regard, the β-ketoacyl ACP synthase KasA is a promising enzyme. In this study, three molecular dynamics simulations based on the wildtype crystal structures of inhibitor bound and unbound KasA were performed in order to investigate the flexibility and conformational space of this target. We present an exhaustive analysis of the binding-site flexibility and representative pocket conformations that may serve as new starting points for structure-based drug design. We also revealed a mechanism which may account for the comparatively low binding affinity of thiolactomycin. Furthermore, we examined the behavior of water molecules within the binding pocket and provide recommendations how to handle them in the drug design process. Finally, we analyzed the dynamics of a channel that accommodates the long-chain fatty acid substrates and, thereby, propose a mechanism of substrate access to this channel and how products are most likely released.
几十年来，抑制分枝杆菌细胞壁必需成分脂肪酸的产生一直是治疗结核病的一种既定方法。然而，不断增加的耐药性和过时的医疗方法需要验证新的靶点，这些靶点涉及到这个关键途径。在这方面，β-酮酰基 ACP 合酶 KasA 是一种很有前途的酶。在这项研究中，我们基于抑制剂结合和未结合的 KasA 的野生型晶体结构进行了三次分子动力学模拟，以研究该靶标的柔韧性和构象空间。我们对结合位点的柔韧性和代表性口袋构象进行了详尽的分析，这些构象可能成为基于结构的药物设计的新起点。我们还揭示了一种可能解释硫乳霉素结合亲和力相对较低的机制。此外，我们研究了结合口袋内水分子的行为，并提供了在药物设计过程中处理这些水分子的建议。最后，我们分析了容纳长链脂肪酸底物的通道的动力学，并提出了一种底物进入该通道的机制，以及产物最有可能释放的方式。
