Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
Eur J Med Chem. 2018 Oct 5;158:733-742. doi: 10.1016/j.ejmech.2018.09.045. Epub 2018 Sep 15.
As promising colchicine binding site inhibitors, SMART and its analogues have attracted many research efforts in recent years. A large number of SMART analogues with different B-rings have been reported; however, the effects of B-ring on the bioactivity are still unclear so far. Herein, we speculated that the conformational preference caused by B-rings was crucial for active SMART analogues. Our assumption was supported by the molecular docking studies, molecular dynamic simulation and DFT computations of SMART and its analogues reported by other and our research groups. Moreover, several novel SMART analogues with different conformational preferences were designed and synthesized to disclose the conformation impacts, and the preliminary biological evaluation was in accordance with our assumption.
作为有前景的秋水仙碱结合位点抑制剂，SMART 及其类似物近年来吸引了众多研究人员的关注。已经报道了大量具有不同 B 环的 SMART 类似物；然而，迄今为止，B 环对生物活性的影响仍不清楚。在此，我们推测 B 环引起的构象偏好对于活性 SMART 类似物至关重要。我们的假设得到了其他和我们研究小组报道的 SMART 及其类似物的分子对接研究、分子动力学模拟和 DFT 计算的支持。此外，设计和合成了几种具有不同构象偏好的新型 SMART 类似物，以揭示构象的影响，初步的生物学评价与我们的假设一致。
