Drug Discovery Platform, Parc Científic Barcelona (PCB), Baldiri Reixac 4-6, E-08028 Barcelona, Spain.
Unit of Glycoconjugate Chemistry, Institut de Química Avançada de Catalunya, I.Q.A.C.-C.S.I.C., Jordi Girona 18-26, E-08034 Barcelona, Spain.
Mol Inform. 2011 Mar 14;30(2-3):161-7. doi: 10.1002/minf.201000157. Epub 2011 Mar 18.
We have previously reported the design and synthesis of ligands that stabilize Transthyretin protein (TTR) in order to obtain therapeutically active compounds for Familial Amyloid Polyneuropathy (FAP). We are hereby reporting a drug design strategy to optimize these ligands and map them in Chemico-Biological Space (CBS) using Ligand Efficiency Indices (LEIs). We use a binding efficiency index (BEI) based on the measured binding affinity related to the molecular weight (MW) of the compound combined with surface-binding efficiency index (SEI) based on Polar Surface Area (PSA). We will illustrate the use of these indices, combining three crucial variables (potency, MW and PSA) in a 2D graphical representation of chemical space, to perform a retrospective mapping of SAR data for a current TTR inhibitors database, and we propose prospective strategies to use these efficiency indices and chemico-biological space maps for optimization and drug design efforts for TTR ligands.
我们之前曾报道过设计和合成稳定转甲状腺素蛋白（TTR）的配体的方法，旨在获得用于家族性淀粉样多发性神经病（FAP）的治疗性有效化合物。在此，我们报告了一种药物设计策略，以优化这些配体，并使用配体效率指数（LEI）在化学-生物空间（CBS）中对其进行映射。我们使用基于结合亲和力与化合物分子量（MW）相关的结合效率指数（BEI），结合基于极性表面积（PSA）的表面结合效率指数（SEI）。我们将结合三个关键变量（效力、MW 和 PSA），在化学空间的 2D 图形表示中，说明这些指数的使用，对当前 TTR 抑制剂数据库的 SAR 数据进行回顾性映射，并提出前瞻性策略，使用这些效率指数和化学-生物空间图进行 TTR 配体的优化和药物设计工作。
