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<p>Caspase-3 activity is a hallmark of apoptosis evasion in many cancers, yet no small-molecule Mirdametinib derivatives have been systematically explored for direct modulation of the caspase-3 catalytic site. Addressing this gap, we employed a structure-based design and multi-scale computational strategy, including molecular docking, ADME/toxicity profiling, density functional theory (DFT), and molecular dynamics (MD) simulations, to design and evaluate 15 novel Mirdametinib derivatives for their ability to restore or enhance caspase-3 function in cancer. Across the 15 derivatives, binding affinities ranged from − 6.3 to − 7.3&#xa0;kcal·mol⁻¹. Compounds-5 and − 6 also showed relatively strong binding (− 7.0&#xa0;kcal·mol⁻¹), whereas the majority (Compounds-1–3, 7–15) displayed comparable or weaker affinities (− 6.3 to − 6.8&#xa0;kcal·mol⁻¹). Among these, Compound-4 demonstrated the most favorable profile, with superior binding affinity (− 7.3&#xa0;kcal·mol⁻¹) compared to the FDA-approved Mirdametinib (− 6.8&#xa0;kcal·mol⁻¹), forming persistent interactions with the catalytic residues Cys163 and His121, suggestive of a direct modulatory role. ADME analysis confirmed the drug-likeness of Compound-4, with high gastrointestinal absorption and no predicted mutagenicity. DFT results showed favorable HOMO–LUMO energy gaps and dipole moments, indicating electronic stability and reactivity. MD simulations over 100 ns revealed that Compound-4 formed a more stable and energetically favorable complex with caspase-3, supported by lower RMSD, reduced solvent exposure, persistent hydrogen bonding, and improved contact fidelity. These findings underscore Compound-4 as a chemically stable, dynamically robust, and pharmacologically promising direct caspase-3 modulator. This work highlights the utility of computational design in developing targeted anticancer therapeutics and lays the groundwork for further experimental validation of Compound-4 in apoptosis-driven cancer therapy.</p> Graphical abstract <p></p>

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Computational design and characterization of some Mirdametinib derivatives as a promising caspase-3 modulator in cancer therapy

  • 期刊论文

  • 发表日期：

    2025年11月4日

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  • Rahul Kumar Singh,
  • Oishi Dhar,
  • Rajesh Kumar Das

摘要

Caspase-3 activity is a hallmark of apoptosis evasion in many cancers, yet no small-molecule Mirdametinib derivatives have been systematically explored for direct modulation of the caspase-3 catalytic site. Addressing this gap, we employed a structure-based design and multi-scale computational strategy, including molecular docking, ADME/toxicity profiling, density functional theory (DFT), and molecular dynamics (MD) simulations, to design and evaluate 15 novel Mirdametinib derivatives for their ability to restore or enhance caspase-3 function in cancer. Across the 15 derivatives, binding affinities ranged from − 6.3 to − 7.3 kcal·mol⁻¹. Compounds-5 and − 6 also showed relatively strong binding (− 7.0 kcal·mol⁻¹), whereas the majority (Compounds-1–3, 7–15) displayed comparable or weaker affinities (− 6.3 to − 6.8 kcal·mol⁻¹). Among these, Compound-4 demonstrated the most favorable profile, with superior binding affinity (− 7.3 kcal·mol⁻¹) compared to the FDA-approved Mirdametinib (− 6.8 kcal·mol⁻¹), forming persistent interactions with the catalytic residues Cys163 and His121, suggestive of a direct modulatory role. ADME analysis confirmed the drug-likeness of Compound-4, with high gastrointestinal absorption and no predicted mutagenicity. DFT results showed favorable HOMO–LUMO energy gaps and dipole moments, indicating electronic stability and reactivity. MD simulations over 100 ns revealed that Compound-4 formed a more stable and energetically favorable complex with caspase-3, supported by lower RMSD, reduced solvent exposure, persistent hydrogen bonding, and improved contact fidelity. These findings underscore Compound-4 as a chemically stable, dynamically robust, and pharmacologically promising direct caspase-3 modulator. This work highlights the utility of computational design in developing targeted anticancer therapeutics and lays the groundwork for further experimental validation of Compound-4 in apoptosis-driven cancer therapy.

Graphical abstract