Said Ahmed M, Hangauer David G
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Helwan, Egypt.
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States.
Bioorg Med Chem Lett. 2016 Aug 15;26(16):3850-4. doi: 10.1016/j.bmcl.2016.07.024. Epub 2016 Jul 9.
Ligand-protein binding is a complex process that involves the formation of number of non-covalent interactions, e.g. H-bonds and hydrophobic interactions, between the ligand and the protein host. Upon binding, ligand functional groups can act synergistically (positive cooperativity) to improve the overall ligand binding affinity beyond what would be expected from their individual contributions. In this study, using thrombin as a protein model system, we evaluated the effect of the bioisosteric replacement of a carbonyl functionality with a sulphonyl functionality on positive cooperativity between their H-bonds with thrombin and hydrophobic binding in the adjacent S3 pocket. The positive cooperativity observed was greatly reduced when replacing the carbonyl group with a sulphonyl group. Evaluating how bioisosteric replacements affect cooperativity is important for making better informed ligand optimization SAR decisions.
配体与蛋白质的结合是一个复杂的过程，涉及配体与蛋白质主体之间形成多种非共价相互作用，例如氢键和疏水相互作用。结合后，配体官能团可以协同作用（正协同效应），以提高整体配体结合亲和力，超出其各自贡献所预期的水平。在本研究中，我们以凝血酶作为蛋白质模型系统，评估了用磺酰基官能团生物电子等排取代羰基官能团对其与凝血酶形成的氢键之间的正协同效应以及相邻S3口袋中疏水结合的影响。用磺酰基取代羰基时，观察到的正协同效应大大降低。评估生物电子等排取代如何影响协同效应对于做出更明智的配体优化构效关系决策很重要。
