Centre for Biodiversity Exploration and Conservation (CBEC), 15, Kundan Residency, 4th Mile Mandla Road, Tilhari, Jabalpur, M.P 482021, India; Indian Institute of Technology Gandhinagar, Palaj Campus, Gujarat 382355, India; School of Sciences, Sanjeev Agrawal Global Educational (SAGE) University, Bhopal, M.P 462022, India; Prof. Wagner A. Vendrame's Laboratory, Environmental Horticulture Department, University of Florida, Institute of Food and Agricultural Sciences, 2550 Hull Rd., Gainesville, FL 32611, USA.
Int J Biol Macromol. 2024 Nov;281(Pt 2):136201. doi: 10.1016/j.ijbiomac.2024.136201. Epub 2024 Oct 4.
Focal Adhesive Kinase (FAK), a key player in aggressive cancers, mediates signals crucial for progression, invasion, and metastasis. Despite advances in targeted therapies, drug resistance is still a challenge, and survival rates remain low, particularly for late-stage patients, emphasizing the need for innovative cancer therapeutics. Cyclopamine, a veratrum alkaloid, has shown promising anti-tumor properties, but the search for more potent analogs with enhanced affinity for the biological target continues. This study employs a hybrid virtual screening approach combining pharmacophore model-based virtual screening (PB-VS) and docking-based virtual screening (DB-VS) to identify potential inhibitors of the FAK catalytic domain. PB-VS on the PubChem database yielded a set of hits, which were then docked with the FAK catalytic domain in two stages (1 and 2 DB-VS). Hits were ranked based on docking scores and interactions with the active site. The top three compounds underwent molecular dynamics simulations, alongside two control compounds (SMO inhibitor(s) and FAK inhibitor(s)), to assess stability through RMSD, RMSF, Rg, and SASA analyses. ADMET properties were evaluated, and compounds were filtered based on drug-likeness criteria. Molecular dynamics simulations demonstrated the stability of compounds when complexed with the FAK catalytic domain. Compounds 16 (-25 kcal/mol), 87 (-27.47 kcal/mol), and 88 (-18.94 kcal/mol) exhibited comparable docking scores, interaction profiles, stability, and binding energies, indicating their potential as lead candidates. However, further validation and optimization through quantitative structure-activity relationship (QSAR) studies are essential to refine their efficacy and therapeutic potential. The in vitro cell-based assay demonstrated that compound 101PF, a FAK inhibitor, significantly inhibited the proliferation and migration of A549 cells. However, the results regarding the combined effects of FAK and SMO inhibitors were inconclusive, highlighting the need for further investigation. This study contributes to developing more effective anti-cancer drugs by improving the understanding of potential cyclopamine-based veratrum alkaloid analogs with enhanced interactions with the FAK catalytic domain.
黏着斑激酶（FAK）是侵袭性癌症的关键因子，它介导着促进肿瘤进展、侵袭和转移的关键信号。尽管靶向治疗取得了进展，但耐药性仍然是一个挑战，生存率仍然很低，特别是对于晚期患者，这强调了需要创新的癌症治疗方法。羊角拗生物碱中的海葱苷，已经显示出有希望的抗肿瘤特性，但仍在寻找具有更高亲和力的更有效的类似物，以针对生物靶标。本研究采用了一种混合虚拟筛选方法，结合基于药效团模型的虚拟筛选（PB-VS）和基于对接的虚拟筛选（DB-VS），以鉴定 FAK 催化结构域的潜在抑制剂。在 PubChem 数据库上进行 PB-VS 筛选得到了一组命中化合物，然后将这些化合物与 FAK 催化结构域进行两次对接（1 和 2 DB-VS）。根据对接得分和与活性位点的相互作用对命中化合物进行排名。前三种化合物与两种对照化合物（SMO 抑制剂和 FAK 抑制剂）一起进行分子动力学模拟，以通过 RMSD、RMSF、Rg 和 SASA 分析评估稳定性。评估了 ADMET 特性，并根据药物相似性标准对化合物进行了筛选。分子动力学模拟表明，当化合物与 FAK 催化结构域结合时，它们是稳定的。化合物 16（-25 kcal/mol）、87（-27.47 kcal/mol）和 88（-18.94 kcal/mol）表现出相当的对接得分、相互作用谱、稳定性和结合能，表明它们具有作为潜在先导化合物的潜力。然而，通过定量构效关系（QSAR）研究进一步验证和优化是必要的，以改善它们的疗效和治疗潜力。基于细胞的体外测定表明，FAK 抑制剂化合物 101PF 显著抑制了 A549 细胞的增殖和迁移。然而，关于 FAK 和 SMO 抑制剂联合作用的结果并不明确，这突出表明需要进一步研究。本研究通过提高对与 FAK 催化结构域具有增强相互作用的潜在海葱苷类羊角拗生物碱类似物的理解，为开发更有效的抗癌药物做出了贡献。
