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，通过调节免疫反应并阻止癌细胞逃避免疫破坏，在癌症治疗中展现出广阔前景。然而，该方法存在免疫系统异常激活并攻击健康细胞的风险。为降低此风险，本研究提出一种基于肿瘤酸性微环境内选择性靶向PD-L1通路的策略。我们采用虚拟筛选、分子力学及分子动力学模拟等计算机模拟方法，对MolPort数据库中约10,000种天然化合物进行分析，以筛选具有目标特性的潜在候选分子。模拟在两种pH条件（pH=7.4和5.5）下进行，以模拟健康细胞与癌细胞的微环境。化合物MolPort-001-742-690显示出作为pH选择性抑制剂的潜力，在酸性条件下对PD-L1具有显著亲和力，且相较于BMS-202和LP23等已知抑制剂毒性更低。长达1000纳秒的分子动力学模拟证实了该抑制剂-PD-L1复合物在酸性条件下的稳定性。本研究凸显了利用计算机模拟技术发现新型pH选择性抑制剂的潜力，这些抑制剂经过实验验证后，有望提高免疫疗法的精准性并降低其毒性，为癌症治疗提供革新性策略。
肿瘤(癌症)患者之家