Pagano Nicholas, Teriete Peter, Mattmann Margrith E, Yang Li, Snyder Beth A, Cai Zhaohui, Heil Marintha L, Cosford Nicholas D P
Cancer Metabolism & Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, United States.
Southern Research Institute, Drug Development Division, 431 Aviation Way, Frederick, MD 21701, United States.
Bioorg Med Chem. 2017 Dec 1;25(23):6248-6265. doi: 10.1016/j.bmc.2017.03.061. Epub 2017 Apr 8.
Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanism of action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents.
采用连续流动（微流控）化学方法制备了一个小型聚焦的二氢嘧啶酮（DHPM）衍生物库。据报道，这类化合物具有抗人类免疫缺陷病毒（HIV）的活性，但其分子靶点尚未确定。我们在表型分析中测试了最初的一组DHPM，得到了一个能够抑制人类免疫缺陷病毒HIV在细胞中复制的活性化合物（1i）。通过流动化学驱动对1i进行优化，鉴定出了HIV复制抑制剂，如1l，其细胞活性与临床药物奈韦拉平（NVP）相当。利用细胞和生化分析、三维指纹图谱和计算机模拟进行的作用机制（MOA）研究表明，这些类药物探针化合物通过抑制病毒逆转录酶聚合酶（RT）发挥作用。这促使我们设计并合成了新型DHPM 1at，它能够抑制HIV耐药菌株的复制。我们的工作表明，将流动化学驱动的类似物优化与表型分析、计算机模拟和MOA研究相结合，是一种从活性化合物到先导化合物优化的高效策略，适用于未来治疗药物的发现。
