Said Ahmed M, Hangauer David G
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
Eur J Med Chem. 2015;96:405-24. doi: 10.1016/j.ejmech.2015.03.059. Epub 2015 Mar 27.
One of the underappreciated non-covalent binding factors, which can significantly affect ligand-protein binding affinity, is the cooperativity between ligand functional groups. Using four different series of thrombin inhibitors, we reveal a strong positive cooperativity between an H-bond accepting carbonyl functionality and the adjacent P3 hydrophobic side chain. Adding an H-bond donating amine adjacent to the P3 hydrophobic side chain further increases this positive cooperativity thereby improving the Ki by as much as 546-fold. In contrast, adding an amidine multiple H-bond/salt bridge group in the distal S1 pocket does not affect this cooperativity. An analysis of the crystallographic B-factors of the ligand groups inside the binding site indicates that the strong cooperativity is mainly due to a significant mutual reduction in the residual mobility of the hydrophobic side chain and the H-bonding functionalities that is absent when the separation distance is large. This type of cooperativity is important to encode in binding affinity prediction software, and to consider in SAR studies.
一种未得到充分重视的非共价结合因素，它可显著影响配体与蛋白质的结合亲和力，即配体官能团之间的协同作用。我们使用四种不同系列的凝血酶抑制剂，揭示了一个氢键接受羰基官能团与相邻的P3疏水侧链之间存在很强的正协同作用。在P3疏水侧链附近添加一个氢键供体胺会进一步增强这种正协同作用，从而使抑制常数（Ki）提高多达546倍。相比之下，在远端S1口袋中添加一个脒基多氢键/盐桥基团并不会影响这种协同作用。对结合位点内配体基团的晶体学B因子分析表明，这种强协同作用主要是由于疏水侧链与氢键官能团的残余流动性显著相互降低，而当分离距离较大时则不存在这种情况。这种协同作用类型对于在结合亲和力预测软件中进行编码以及在构效关系（SAR）研究中加以考虑非常重要。
