Pharmaceutical Design and Simulation (PhDS) Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia , 11800 Minden, Pulau Pinang, Malaysia.
J Chem Inf Model. 2013 Sep 23;53(9):2423-36. doi: 10.1021/ci400421e. Epub 2013 Sep 13.
ProBiS is a new method to identify the binding site of protein through local structural alignment against the nonredundant Protein Data Bank (PDB), which may result in unique findings compared to the energy-based, geometry-based, and sequence-based predictors. In this work, binding sites of Hemagglutinin (HA), which is an important target for drugs and vaccines in influenza treatment, have been revisited by ProBiS. For the first time, the identification of conserved binding sites by local structural alignment across all subtypes and strains of HA available in PDB is presented. ProBiS finds three distinctive conserved sites on HA's structure (named Site 1, Site 2, and Site 3). Compared to other predictors, ProBiS is the only one that accurately defines the receptor binding site (Site 1). Apart from that, Site 2, which is located slightly above the TBHQ binding site, is proposed as a potential novel conserved target for membrane fusion inhibitor. Lastly, Site 3, located around Helix A at the stem domain and recently targeted by cross-reactive antibodies, is predicted to be conserved in the latest H7N9 China 2013 strain as well. The further exploration of these three sites provides valuable insight in optimizing the influenza drug and vaccine development.
ProBiS 是一种通过与非冗余蛋白质数据库 (PDB) 中的局部结构比对来识别蛋白质结合位点的新方法，与基于能量、基于几何形状和基于序列的预测器相比，它可能会产生独特的发现。在这项工作中，ProBiS 重新研究了血凝素 (HA) 的结合位点，HA 是流感治疗中药物和疫苗的重要靶点。首次提出了通过 PDB 中所有亚型和株 HA 的局部结构比对来识别保守结合位点的方法。ProBiS 在 HA 的结构上发现了三个独特的保守位点 (命名为 Site 1、Site 2 和 Site 3)。与其他预测器相比，ProBiS 是唯一能准确定义受体结合位点 (Site 1) 的方法。除此之外，位于 TBHQ 结合位点上方的 Site 2 被提议作为膜融合抑制剂的潜在新保守靶标。最后，位于茎域 A 螺旋周围的 Site 3 最近被交叉反应性抗体靶向，预计在最新的 H7N9 中国 2013 株中也能保守。对这三个位点的进一步探索为优化流感药物和疫苗的开发提供了有价值的见解。
