Results of Molecular Docking.

Cystic Fibrosis (CF) is a hereditary condition and can cause permanent respiration problems leading to degraded life quality. The most common variation leading to CF is the F508del variation. CF can cause damage to not just the lungs but also digestive system, pancreas, and other organs. CF decreases the life expectancy of the individuals affected with the constant fear of lung complications. The current methods of treatment include using a combination of drugs to manage the symptoms. The combination of drugs has many side effects and causes damage to other organs like liver, heart or kidneys. In this study, we aim to find a drug that can relieve the symptoms of CF. We began by creating a dataset of potential drug molecules, which was subsequently refined by removing harmful compounds through an ADMET scan. All these compounds were then docked to the mutated Cystic Fibrosis Transmembrane Regulator (CFTR) protein. The compounds with the best docking affinity were Galicaftor and Bamocaftor. A currently approved drug, Ivacaftor was selected as control for the 200 ns Molecular Dynamics (MD) Simulation. The simulation revealed that the CFTR protein remained more stable and compact when complexed with Bamocaftor, when compared to Ivacaftor and Galicaftor. Moreover, the MMPBSA free energy calculations revealed that the free energy of the CFTR-bamocaftor complex is the lowest compared to the other complexes. Our findings reveal the action of bamocaftor on CFTR protein with p.Phe508del variation. However, the absence of in-vivo or in-vitro studies is a limitation, and further experimental validation is necessary to confirm its efficacy and safety.囊性纤维化（Cystic Fibrosis, CF）是一种遗传性疾病，可引发永久性呼吸功能障碍，进而导致生活质量下降。引发CF最常见的基因突变类型为F508del突变。CF不仅会损伤肺部，还可累及消化系统、胰腺及其他器官；患者不仅寿命缩短，还长期面临肺部并发症的威胁。当前临床治疗多采用联合用药方案以控制症状，但此类疗法存在诸多不良反应，还可能对肝脏、心脏、肾脏等其他器官造成损伤。本研究旨在筛选可缓解CF症状的潜在药物。我们首先构建了潜在药物分子数据集，随后通过ADMET扫描剔除其中的有害化合物。将所有剩余化合物与突变型囊性纤维化跨膜传导调节因子（Cystic Fibrosis Transmembrane Regulator, CFTR）进行分子对接，最终筛选出对接亲和力最优的两个化合物：加拉他福（Galicaftor）与巴莫卡福（Bamocaftor）。选取已获批上市的依伐卡托（Ivacaftor）作为对照，开展200纳秒分子动力学（Molecular Dynamics, MD）模拟。模拟结果显示，相较于依伐卡托与加拉他福，巴莫卡福与CFTR蛋白形成的复合物可使蛋白保持更稳定、更紧凑的构象。此外，MMPBSA自由能计算结果表明，CFTR-巴莫卡福复合物的自由能低于其余各组复合物。本研究阐明了巴莫卡福对携带p.Phe508del突变的CFTR蛋白的作用机制。但本研究尚未开展体内（in-vivo）或体外（in-vitro）实验，存在一定局限性，后续需通过实验验证其疗效与安全性。