迫切需要开发新的,更安全,和更有效的药物对抗查加斯病(CD)以及相关的动体疾病。在这种情况下,靶向和抑制锥虫蛋白酶体已成为一种有前途的治疗方法。为了扩大这类抑制剂的化学空间,我们进行了虚拟筛查活动,重点是基于形状的相似性和ADMET优先排序.我们描述了这些活动的可靠验证形状查询的构想和应用,为生物评价提供了44种化合物。五个命中化合物通过潜在抑制克氏锥虫蛋白酶体和显着的化学多样性证明了体外抗锥虫活性,特别是,LCQFTC11。通过同源性建模实现了结构洞察,序列/结构比对,蛋白酶体-物种比较,对接,分子动力学,和MMGBSA结合亲和力估计。这些方法证实了关键相互作用以及LCQFTC11在克氏锥虫蛋白酶体β4/β5亚基结合位点的稳定性,与已知的抑制剂一致。我们的结果保证了我们作为克氏T.cruzi蛋白酶体抑制剂的命中的未来测定证实。重要的是,我们还揭示了蛋白酶体抑制机制的动态细节,这将进一步研究。我们期望通过这种相关方法为开发可行的CD候选药物做出贡献。
There is an urgent need to develop new, safer, and more effective drugs against Chagas disease (CD) as well as related kinetoplastid diseases. Targeting and inhibiting the Trypanosoma cruzi
proteasome has emerged as a promising therapeutic approach in this context. To expand the chemical space for this class of inhibitors, we performed virtual screening campaigns with emphasis on shape-based similarity and ADMET prioritization. We describe the ideation and application of robustly validated shape queries for these campaigns, which furnished 44 compounds for biological evaluation. Five hit compounds demonstrated in vitro antitrypanosomal activity by potential inhibition of T. cruzi
proteasome and notable chemical diversities, particularly, LCQFTC11. Structural insights were achieved by homology modeling, sequence/structure alignment,
proteasome-species comparison, docking, molecular dynamics, and MMGBSA binding affinity estimations. These methods confirmed key interactions as well as the stability of LCQFTC11 at the β4/β5 subunits\' binding site of the T. cruzi proteasome, consistent with known inhibitors. Our results warrant future assay confirmation of our hit as a T. cruzi
proteasome inhibitor. Importantly, we also shed light into dynamic details for a
proteasome inhibition mechanism that shall be further investigated. We expect to contribute to the development of viable CD drug candidates through such a relevant approach.