Wang L, Duan Y, Stouten P, De Lucca G V, Klabe R M, Kollman P A
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
J Comput Aided Mol Des. 2001 Feb;15(2):145-56. doi: 10.1023/a:1008156222963.
The cyclic urea inhibitors of HIV-1 protease generally have two hydroxyl groups on the seven-membered ring. In this study, free energy perturbation and continuum electrostatic calculations were used to study the contributions of the two hydroxyl groups to the binding affinity and solubility of a cyclic urea inhibitor DMP323. The results indicated that the inhibitor with one hydroxyl group has better binding affinity and solubility than the inhibitor with two hydroxyl groups. Therefore, removal of one hydroxyl group from DMP323 may help to improve the properties of DMP323. This is also likely to be true for other cyclic urea inhibitors. The study also illustrated the difficulty in accurate modeling of the binding affinities of HIV-1 protease inhibitors, which involves many possible protonation states of the two catalytic aspartic acids in the active site of the enzyme.
HIV-1蛋白酶的环状尿素抑制剂通常在七元环上有两个羟基。在本研究中，采用自由能扰动和连续介质静电计算来研究这两个羟基对环状尿素抑制剂DMP323结合亲和力和溶解度的贡献。结果表明，含有一个羟基的抑制剂比含有两个羟基的抑制剂具有更好的结合亲和力和溶解度。因此，从DMP323中去除一个羟基可能有助于改善DMP323的性质。这对于其他环状尿素抑制剂可能也是如此。该研究还说明了准确模拟HIV-1蛋白酶抑制剂结合亲和力的困难，这涉及到酶活性位点中两个催化天冬氨酸的许多可能质子化状态。
