Alam Aftab, Alqarni Mohammed H, Singh Indrakant K, Foudah Ahmed I, Upmanyu Neeraj, Balaha Mohamed F
Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
Molecular Biology Research Lab, Department of Zoology, Deshbandhu College, University of Delhi, Delhi, India.
Curr Pharm Des. 2025 Mar 11. doi: 10.2174/0113816128342778250218105338.
Anaplastic Lymphoma Kinase (ALK) is implicated in several cancers, including anaplastic large cell lymphoma, non-small cell lung cancer, and neuroblastoma. Targeted inhibition of ALK represents a promising therapeutic strategy.
This study aimed to identify and evaluate potential ALK inhibitors using virtual screening and computational analyses to determine their binding stability, affinity, and dynamic behavior, ultimately assessing their potential as therapeutic agents for ALK-driven cancers.
The objective of this study was to identify potential ALK inhibitors using virtual screening techniques and to evaluate their binding affinities and stability through computational analyses.
This study utilized virtual screening to identify potential ALK inhibitors from the MTiOpen Screen Diverse library and selected three compounds (24331480, 26536128, and 24353407) based on their binding affinities. These compounds underwent optimization using Density Functional Theory (DFT) and were redocked to confirm binding stability. Molecular dynamics simulations, hydrogen bond analysis, MM/PBSA calculations, and PCA-based free energy landscape analysis were also carried out.
The re-docking experiments confirmed the stable and strong binding affinities of the selected compounds to the ALK active site. Molecular dynamics simulations revealed stable interactions throughout the 200 ns simulation period. Hydrogen bond analysis demonstrated consistent hydrogen bonds between key residues and the inhibitors. MM/PBSA calculations indicated favorable binding free energies, suggesting strong binding affinities. Finally, PCA-based free energy landscape analysis highlighted energetically favorable binding modes.
The identified compounds (24331480, 26536128, and 24353407) exhibited promising inhibitory potential against ALK. These findings warrant further experimental validation to confirm their potential as therapeutic agents for ALK-driven cancers.
间变性淋巴瘤激酶（ALK）与多种癌症有关，包括间变性大细胞淋巴瘤、非小细胞肺癌和神经母细胞瘤。对ALK的靶向抑制是一种有前景的治疗策略。
本研究旨在通过虚拟筛选和计算分析来识别和评估潜在的ALK抑制剂，以确定它们的结合稳定性、亲和力和动态行为，最终评估它们作为ALK驱动癌症治疗药物的潜力。
本研究的目标是使用虚拟筛选技术识别潜在的ALK抑制剂，并通过计算分析评估它们的结合亲和力和稳定性。
本研究利用虚拟筛选从MTiOpen Screen Diverse文库中识别潜在的ALK抑制剂，并根据它们的结合亲和力选择了三种化合物（24331480、26536128和24353407）。这些化合物使用密度泛函理论（DFT）进行优化，并重新对接以确认结合稳定性。还进行了分子动力学模拟、氢键分析、MM/PBSA计算和基于主成分分析的自由能景观分析。
重新对接实验证实了所选化合物与ALK活性位点的稳定和强结合亲和力。分子动力学模拟显示在整个200 ns模拟期内相互作用稳定。氢键分析表明关键残基与抑制剂之间存在一致的氢键。MM/PBSA计算表明结合自由能有利，表明结合亲和力强。最后，基于主成分分析的自由能景观分析突出了能量上有利的结合模式。
所鉴定的化合物（24331480、26536128和24353407）对ALK表现出有前景的抑制潜力。这些发现值得进一步的实验验证，以确认它们作为ALK驱动癌症治疗药物的潜力。
