Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Saulėtekio al. 7, Vilnius LT-10257, Lithuania.
Department of Protein - DNA Interactions, Institute of Biotechnology, Vilnius University, Saulėtekio al. 7, Vilnius LT-10257, Lithuania.
Eur J Med Chem. 2018 Aug 5;156:61-78. doi: 10.1016/j.ejmech.2018.06.059. Epub 2018 Jun 27.
Rational design of compounds that would bind specific pockets of the target proteins is a difficult task in drug design. The 12 isoforms of catalytically active human carbonic anhydrases (CAs) have highly similar active sites that make it difficult to design inhibitors selective for one or several CA isoforms. A series of CA inhibitors based on 2-chloro/bromo-benzenesulfonamide that is largely fixed in the CA active site together with one or two tails yielded compounds that were synthesized and evaluated as inhibitors of CA isoforms. Introduction of a second tail had significant influence on the binding affinity and two-tailed compounds in most cases provided high affinity and selectivity for CA IX and CA XIV. The contacts between several compounds and CA amino acids were determined by X-ray crystallography. Together with the intrinsic enthalpy and entropy of binding they provided the structure-thermodynamics correlations for this series of compounds with the insight how to rationally build compounds with desired CA isoform as a target.
设计能够与靶蛋白特定口袋结合的化合物是药物设计中的一项艰巨任务。人碳酸酐酶（CA）的 12 种同工酶具有高度相似的活性位点，这使得设计对一种或几种 CA 同工酶具有选择性的抑制剂变得困难。一系列基于 2-氯/溴苯磺酰胺的 CA 抑制剂，其在 CA 活性位点中基本固定，同时带有一个或两个尾巴，得到了合成并评估为 CA 同工酶抑制剂的化合物。引入第二个尾巴对结合亲和力有显著影响，在大多数情况下，双尾化合物对 CAIX 和 CAXIV 具有高亲和力和选择性。通过 X 射线晶体学确定了几种化合物与 CA 氨基酸之间的接触。结合结合的固有焓和熵，它们为这一系列化合物提供了结构热力学相关性，深入了解如何合理构建以所需 CA 同工酶为靶标的化合物。
