Lam P Y, Ru Y, Jadhav P K, Aldrich P E, DeLucca G V, Eyermann C J, Chang C H, Emmett G, Holler E R, Daneker W F, Li L, Confalone P N, McHugh R J, Han Q, Li R, Markwalder J A, Seitz S P, Sharpe T R, Bacheler L T, Rayner M M, Klabe R M, Shum L, Winslow D L, Kornhauser D M, Hodge C N
DuPont Merck Pharmaceutical Company, DuPont Merck Experimental Station, Wilmington, Delaware 19880-0500, USA.
J Med Chem. 1996 Aug 30;39(18):3514-25. doi: 10.1021/jm9602571.
High-resolution X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure-activity relationships of C2-symmetric diol inhibitors, computed-aided drug design tools, and first principles, we designed and synthesized a novel class of cyclic ureas that incorporates this structural water and preorganizes the side chain residues into optimum binding conformations. Conformational analysis suggested a preference for pseudodiaxial benzylic and pseudodiequatorial hydroxyl substituents and an enantiomeric preference for the RSSR stereochemistry. The X-ray and solution NMR structure of the complex of HIV-1PR and one such cyclic urea, DMP323, confirmed the displacement of the structural water. Additionally, the bound and "unbound" (small-molecule X-ray) ligands have similar conformations. The high degree of preorganization, the complementarity, and the entropic gain of water displacement are proposed to explain the high affinity of these small molecules for the enzyme. The small size probably contributes to the observed good oral bioavailability in animals. Extensive structure-based optimization of the side chains that fill the S2 and S2' pockets of the enzyme resulted in DMP323, which was studied in phase I clinical trials but found to suffer from variable pharmacokinetics in man. This report details the synthesis, conformational analysis, structure-activity relationships, and molecular recognition of this series of C2-symmetry HIV-1PR inhibitors. An initial series of cyclic ureas containing nonsymmetric P2/P2' is also discussed.
人免疫缺陷病毒1型蛋白酶（HIV-1PR）与拟肽抑制剂复合物的高分辨率X射线结构显示，存在一个结构水分子，它与该酶的两个可移动侧翼以及抑制剂过渡态模拟物两侧的两个羰基形成氢键。利用C2对称二醇抑制剂的构效关系、计算机辅助药物设计工具和第一原理，我们设计并合成了一类新型的环状脲，它包含了这个结构水分子，并将侧链残基预组织成最佳的结合构象。构象分析表明，该结构更倾向于伪双轴苄基和伪双平伏羟基取代基，并且对RSSR立体化学具有对映体偏好。HIV-1PR与一种这样的环状脲DMP323复合物的X射线和溶液核磁共振结构证实了结构水分子的位移。此外，结合态和“未结合”（小分子X射线）配体具有相似的构象。预组织程度高、互补性以及水位移带来的熵增被认为可以解释这些小分子对该酶的高亲和力。小分子的尺寸可能有助于其在动物体内表现出良好的口服生物利用度。对填充该酶S2和S2'口袋的侧链进行广泛的基于结构的优化，得到了DMP323，它已进入I期临床试验，但发现其在人体中的药代动力学存在差异。本报告详细介绍了这一系列C2对称HIV-1PR抑制剂的合成、构象分析、构效关系和分子识别。还讨论了一系列含有不对称P2/P2'的环状脲。
