McDowell Roderick C, Booth Jordhan D, McGowan Allyson, Kolodziejczyk Wojciech, Hill Glake A, Banerjee Santanu, Feng Manliang, Kapusta Karina
Department of Chemistry, Physics and Atmospheric Sciences, Jackson State University, Jackson, MS 39217, USA.
Department of Chemistry and Physics, Tougaloo College, Tougaloo, MS 39174, USA.
Cancers (Basel). 2024 Jun 22;16(13):2295. doi: 10.3390/cancers16132295.
Immunotherapy, particularly targeting the PD-1/PD-L1 pathway, holds promise in cancer treatment by regulating the immune response and preventing cancer cells from evading immune destruction. Nonetheless, this approach poses a risk of unwanted immune system activation against healthy cells. To minimize this risk, our study proposes a strategy based on selective targeting of the PD-L1 pathway within the acidic microenvironment of tumors. We employed in silico methods, such as virtual screening, molecular mechanics, and molecular dynamics simulations, analyzing approximately 10,000 natural compounds from the MolPort database to find potential hits with the desired properties. The simulations were conducted under two pH conditions (pH = 7.4 and 5.5) to mimic the environments of healthy and cancerous cells. The compound MolPort-001-742-690 emerged as a promising pH-selective inhibitor, showing a significant affinity for PD-L1 in acidic conditions and lower toxicity compared to known inhibitors like BMS-202 and LP23. A detailed 1000 ns molecular dynamics simulation confirmed the stability of the inhibitor-PD-L1 complex under acidic conditions. This research highlights the potential of using in silico techniques to discover novel pH-selective inhibitors, which, after experimental validation, may enhance the precision and reduce the toxicity of immunotherapies, offering a transformative approach to cancer treatment.
免疫疗法，特别是针对PD-1/PD-L1通路的疗法，通过调节免疫反应和防止癌细胞逃避免疫破坏，在癌症治疗中具有前景。然而，这种方法存在对健康细胞产生不必要的免疫系统激活的风险。为了将这种风险降至最低，我们的研究提出了一种基于在肿瘤酸性微环境中选择性靶向PD-L1通路的策略。我们采用了计算机模拟方法，如虚拟筛选、分子力学和分子动力学模拟，分析了来自MolPort数据库的约10,000种天然化合物，以寻找具有所需特性的潜在命中物。模拟在两种pH条件（pH = 7.4和5.5）下进行，以模拟健康细胞和癌细胞的环境。化合物MolPort-001-742-690成为一种有前景的pH选择性抑制剂，在酸性条件下对PD-L1表现出显著亲和力，与BMS-202和LP23等已知抑制剂相比毒性更低。详细的1000 ns分子动力学模拟证实了抑制剂-PD-L1复合物在酸性条件下的稳定性。这项研究突出了使用计算机模拟技术发现新型pH选择性抑制剂的潜力，经过实验验证后，这些抑制剂可能会提高免疫疗法的精准度并降低毒性，为癌症治疗提供一种变革性方法。
