Dai Yingqi, Zhang Yanyan, Gao Shuchun, Sun Tao
Department of Thyroid and Breast Surgery, Shandong Provincial Third Hospital, Shandong University, No.11, Wuyingshanzhong, Tianqiao District, Jinan, 250031, China.
Breast Disease Treatment Centre, Central Hospital Affiliated to Shandong First Medical University, No. 105, Jiefang Road Shandong Province, Jinan City, 250013, China.
J Mol Model. 2025 Aug 30;31(9):262. doi: 10.1007/s00894-025-06479-5.
Breast cancer metastasis remains a significant challenge in oncology, necessitating novel therapeutic approaches. Rac1 is a small GTPase involved in Wnt-planar cell polarity (Wnt-PCP) signaling and modulation of endoplasmic reticulum (ER) stress, and it has emerged as a promising target for inhibiting cancer progression. This study investigates the potential of cinnamaldehyde, a bioactive compound derived from cinnamon bark, as a potential Rac1 inhibitor. Computational analyses reveal that cinnamaldehyde exhibits higher binding specificity and efficacy to Rac1 than a reference inhibitor. Molecular dynamics (MD) simulations, essential dynamics, and MM-PBSA further confirm its stable binding with minimal impact on Rac1's structural conformation, which supports its potential as a lead compound for breast cancer therapy.
A molecular docking study was performed using InstaDock and AutoDock Tools to assess cinnamaldehyde's binding affinity for Rac1. Pharmacokinetic properties were evaluated through SwissADME, and the PASS online tool was used for activity prediction. Protein-ligand interaction analyses were conducted using Discovery Studio Visualizer. All-atom MD simulations were performed for 500 ns using the GROMACS 2022 package with the CHARMM36 force field to analyze the stability of the cinnamaldehyde-Rac1 complex. The binding free energy computations were performed using the MM-PBSA approach.
乳腺癌转移仍然是肿瘤学中的一项重大挑战，需要新的治疗方法。Rac1是一种小GTP酶，参与Wnt-平面细胞极性（Wnt-PCP）信号传导和内质网（ER）应激调节，已成为抑制癌症进展的一个有前景的靶点。本研究调查了肉桂醛（一种从肉桂树皮中提取的生物活性化合物）作为潜在Rac1抑制剂的潜力。计算分析表明，肉桂醛对Rac1的结合特异性和效力高于参考抑制剂。分子动力学（MD）模拟、主成分动力学分析和MM-PBSA进一步证实了其与Rac1的稳定结合，对Rac1的结构构象影响最小，这支持了其作为乳腺癌治疗先导化合物的潜力。
使用InstaDock和AutoDock Tools进行分子对接研究，以评估肉桂醛对Rac1的结合亲和力。通过SwissADME评估药代动力学性质，并使用PASS在线工具进行活性预测。使用Discovery Studio Visualizer进行蛋白质-配体相互作用分析。使用GROMACS 2022软件包和CHARMM36力场进行500 ns的全原子MD模拟，以分析肉桂醛-Rac1复合物的稳定性。使用MM-PBSA方法进行结合自由能计算。
