Negi Preeya, Swaroop Akey Krishna, Singh Anuj Kumar, Rajan Saranya, Mariappan Esakkimuthukumar, Palanimuthu Vasanth Raj, Natarajan Jawahar, Selvaraj Jubie
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Ootacamund, Tamil Nadu, 643001, India.
Department of Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Ootacamund, Tamil Nadu, 643001, India.
Protein Pept Lett. 2025;32(4):253-268. doi: 10.2174/0109298665361116250121103146.
This study compares the activity of BRCA-1 mimetics on WTp53 (wild-type p53 protein) and MTp53 (mutated-type p53 protein) proteins, examining the impact of TP53 mutations in breast cancer. p53 activators can be a new insight and synthesis of effective compounds for the treatment of cancer. The project contributes to the growing body of research on p53 activators and provides new insights into the design and synthesis of effective compounds for the treatment of cancer.
Molecular docking predicted binding affinity values for WTp53 and MTp53. The MMGBSA of top compounds was run to get binding-free energies. The MD simulations were calculated, and six metal coordinates were synthesized. MTT-assays were performed with WTp53 (MCF-7) and R273H-MTp53 (MDA-MB-468) cell lines, comparing results with known p53 activator PRIMA-1 (p53-reactivation and induction of massive apoptosis-1).
The p53 activators established a three-featured (2RA, 1HBA) pharmacophore. The designed compounds had better Glide gscore compared to p53 activators PRIMA-1, PRIMA-1- MET (methylated PRIMA-1), and Tamoxifen with p53 protein (WTp53, R175H and R273H MTp53). The MM-GBSA results of top compounds showed binding free energies with R175HMTp53 (-22.24 to -75.45 kcal/mol), R273H-MTp53 (-22.8 to -36.36 kcal/mol), and WTp53 (-26.45 to -50.3 kcal/mol) compared to the p53 activator. The MD simulation of TSCO5/3KMD-MT in 100 ns indicated a stable complex when compared to TSCO5/3KMD-WT. The six metal coordinates (TSCO5-Zn, TSCO6-Zn, TSCO6-Sn, TSCO13-Zn, TSCO13-Sn, TSCO9-Sn) were synthesised. Based on results, IC for TSCO5-Zn (WTp53: 0.089 μM, MTp53: 0.074 μM) and TSCO5- Sn (WTp53: 0.092 μM, MTp53: 0.073 μM) have shown significant cytotoxicity.
As compared to PRIMA-1, the designed compound TSCO5 metal coordinates have shown good and in vitro activity on mutated p53 cell lines and are more potent than the p53 activator PRIMA-1.
本研究比较了BRCA-1模拟物对野生型p53（WTp53）和突变型p53（MTp53）蛋白的活性，探讨TP53突变在乳腺癌中的影响。p53激活剂可能为癌症治疗提供新的见解并合成有效的化合物。该项目有助于增加对p53激活剂的研究，并为癌症治疗有效化合物的设计和合成提供新的见解。
分子对接预测WTp53和MTp53的结合亲和力值。运行顶级化合物的MMGBSA以获得结合自由能。计算分子动力学模拟，并合成六个金属配合物。用WTp53（MCF-7）和R273H-MTp53（MDA-MB-468）细胞系进行MTT分析，并将结果与已知的p53激活剂PRIMA-1（p53再激活和大量凋亡诱导剂-1）进行比较。
p53激活剂建立了一个具有三个特征（2个受体激动剂、1个氢键受体）的药效团。与p53激活剂PRIMA-1、PRIMA-1-MET（甲基化PRIMA-1）和他莫昔芬与p53蛋白（WTp53、R175H和R273H MTp53）相比，设计的化合物具有更好的Glide评分。顶级化合物的MM-GBSA结果显示，与p53激活剂相比，R175HMTp53（-22.24至-75.45千卡/摩尔）、R273H-MTp53（-22.8至-36.36千卡/摩尔）和WTp53（-26.45至-50.3千卡/摩尔）的结合自由能。TSCO5/3KMD-MT在100纳秒内的分子动力学模拟表明，与TSCO5/3KMD-WT相比，其复合物更稳定。合成了六个金属配合物（TSCO5-Zn、TSCO6-Zn、TSCO6-Sn、TSCO13-Zn、TSCO13-Sn、TSCO9-Sn）。根据结果，TSCO5-Zn（WTp53：0.089微摩尔，MTp53：0.074微摩尔）和TSCO5-Sn（WTp53：0.092微摩尔，MTp53：0.073微摩尔）的半数抑制浓度显示出显著的细胞毒性。
与PRIMA-1相比，设计的化合物TSCO5金属配合物对突变型p53细胞系显示出良好的体外活性，并且比p53激活剂PRIMA-1更有效。
