Unveiling novel type 1 inhibitors for targeting LIM kinase 2 (LIMK2) for cancer therapeutics: An integrative pharmacoinformatics approach.

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.