Structure-Guided Design of Isoform-Selective LIMK1 Inhibitors: A Peptidomimetic Screening Approach with Molecular Dynamics and Quantum Mechanical Characterization

LIM kinases (LIMK1/2) play critical roles in regulating cytoskeletal dynamics and mitosis, making them attractive targets for cancer therapy. However, most existing LIMK inhibitors lack isoform specificity, often affecting both LIMK1 and LIMK2 due to the high sequence and structural similarity between their kinase domains. This nonselectivity necessitates higher dosing and contributes to undesirable off-target effects, underscoring the need for highly selective LIMK1 inhibitors with better safety profiles. In this study, we aimed to identify potential isoform-selective LIMK1 inhibitors using an integrated structural bioinformatics approach. A focused virtual screening of peptidomimetic libraries was performed against the LIMK1 structure, followed by an evaluation of binding energy using MM/GBSA and molecular dynamics simulations (MDS) to assess interaction stability. Out of 172 initial hits, three top-ranking compounds, namely, ChemDivF594-0457, ChemDivF594-0453 and ChemDivP223-1466, were shortlisted based on their favorable docking scores (−6.85 to −6.46 kcal/mol), strong binding free energies (−62.33 to −48.02 kcal/mol) and predicted pharmacokinetic and toxicity profiles. These candidates exhibited stable binding conformations over a 200 ns simulation period, with key interactions involving conserved residues in the LIMK1 active site. Quantum mechanical (QM) calculations, including HOMO–LUMO analysis, further supported the electronic suitability and reactivity of the selected molecules. Overall, our findings present promising peptidomimetic scaffolds with favorable in silico profiles for LIMK1 inhibition. These candidates warrant further in vitro and in vivo validation to confirm their selectivity and therapeutic potential in LIMK1-driven cancers.