Hemavathy Nagarajan, Umashankar Vetrivel, Jeyakanthan Jeyaraman
Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi, Tamil Nadu 630 003, India.
Virology & Biotechnology/Bioinformatics Division, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu 600 031, India.
Comput Biol Chem. 2025 Apr;115:108289. doi: 10.1016/j.compbiolchem.2024.108289. Epub 2024 Nov 23.
LIMK2 is crucial in regulating actin cytoskeleton dynamics, significantly contributing to cancer cell proliferation, invasion, and metastasis. Inhibitors like LIMKi3 effectively suppress LIMK2 kinase activity by directly affecting actin polymerization and preventing the formation of structures like filopodia and lamellipodia, which are typical of motile cancer cells. By modulating these actin dynamics, LIMKi3 inhibits cancer cell migration and invasion, reducing the potential for metastasis. Thus, this study aims to explore potential anti-cancer therapeutic LIMK2 inhibitors with properties resembling LIMKi3. Henceforth, molecular docking was utilized in this study to comprehend the ATP mimetic binding mode of LIMKi3, followed by Pharmacophore-based virtual screening to identify small molecules resembling LIMKi3. In addition, molecular dynamics simulations were performed to explore the dynamic behavior of LIMK2 and potential inhibitors. Further, network analysis and binding free energy calculations were implemented to comprehensively assess the interactions between the compounds and LIMK2. In molecular docking, LIMKi3 demonstrated an ATP mimetic hinge binding mode with hydrogen bonds at Ile408. Among the screened compounds (NCI300395, ChemDiv-8020-2508, and ChemDiv-7997-0024), three displayed "ADRH" pharmacophoric features like LIMKi3, with favorable ADMET properties, higher binding affinity, and significant hydrogen bond interactions at Ile408. LIMK2-inhibitor complexes showed lower RMSD than LIMK2-LIMKi3, indicating higher equilibrium by identified compounds. Protein-drug Complexes exhibited significant inter-domain correlation in N-lobe residues of LIMK2, including conserved β3, αC, and Hinge residues. Binding free energy analysis ranked LIMK2-NCI300395 highest, followed by LIMK2-ChemDiv-7997-0024 and LIMK2-ChemDiv-8020-2508, highlighting their potential as effective LIMK2-targeting compounds. Hence, this study emphasizes LIMKi3's significance and identifies potential candidates (NCI300395, ChemDiv-7997-0024, and ChemDiv-8020-2508) for developing cancer therapeutics targeting LIMK2. These findings open avenues for further investigations into the complex interplay between cytoskeletal dynamics and cancer progression.
LIMK2在调节肌动蛋白细胞骨架动力学中起关键作用，对癌细胞的增殖、侵袭和转移有显著影响。像LIMKi3这样的抑制剂通过直接影响肌动蛋白聚合，阻止丝状伪足和片状伪足等结构的形成，从而有效抑制LIMK2激酶活性，而这些结构是运动性癌细胞的典型特征。通过调节这些肌动蛋白动力学，LIMKi3抑制癌细胞的迁移和侵袭，降低转移的可能性。因此，本研究旨在探索具有类似LIMKi3特性的潜在抗癌治疗性LIMK2抑制剂。此后，本研究利用分子对接来理解LIMKi3的ATP模拟物结合模式，随后进行基于药效团的虚拟筛选以识别类似LIMKi3的小分子。此外，进行分子动力学模拟以探索LIMK2和潜在抑制剂的动态行为。进一步地，实施网络分析和结合自由能计算以全面评估化合物与LIMK2之间的相互作用。在分子对接中，LIMKi3在Ile408处通过氢键表现出ATP模拟物铰链结合模式。在筛选出的化合物（NCI300395、ChemDiv - 8020 - 2508和ChemDiv - 7997 - 0024）中，有三种表现出类似LIMKi3的“ADRH”药效团特征，具有良好的ADMET性质、更高的结合亲和力以及在Ile408处有显著的氢键相互作用。LIMK2 - 抑制剂复合物的均方根偏差（RMSD）低于LIMK2 - LIMKi3，表明所鉴定的化合物具有更高的平衡稳定性。蛋白质 - 药物复合物在LIMK2的N叶残基中表现出显著的域间相关性，包括保守的β3、αC和铰链残基。结合自由能分析将LIMK2 - NCI300395排在首位,其次是LIMK2 - ChemDiv - 7997 - 0024和LIMK2 - ChemDiv - 8020 - 2508，突出了它们作为有效的LIMK2靶向化合物的潜力。因此，本研究强调了LIMKi3的重要性，并鉴定出潜在的候选物（NCI300395、ChemDiv - 7997 - 0024和ChemDiv - 8020 - 2508）用于开发针对LIMK2的癌症治疗药物。这些发现为进一步研究细胞骨架动力学与癌症进展之间的复杂相互作用开辟了道路。
