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<p>The previously synthesized symmetrical tetradentate bis(benzimidazole) diamide ligand N, N′-bis(1&#xa0;H-benzimidazol-2-ylmethyl)octanediamide (GA1) was investigated using an integrated DFT, spectroscopic, ADME, molecular docking, molecular dynamics, and MM/GBSA approach to clarify the structure–electronics–recognition features of its benzimidazole–diamide framework. Geometry optimization at the B3LYP-D4/def2-TZVP level reveals an extended pseudo-symmetric conformation stabilized by intramolecular N–H···O hydrogen bonds, with the flexible octanediamide linker separating the two benzimidazole termini and preventing intramolecular π–π stacking. Frontier orbital analysis gives a HOMO–LUMO gap of 5.52&#xa0;eV, indicating global electronic stability, while M06-2X and ωB97X-D single-point benchmarks confirm that the frontier orbital localization remains concentrated over the benzimidazole/amide regions. NMR and IR spectral comparisons support the optimized geometry and principal functional-group assignments, particularly the amide C = O and benzimidazole/aromatic regions. MESP, Fukui/dual-descriptor, NPA, and NBO analyses consistently identify the amide carbonyl groups, N–H donor sites, and benzimidazole π-framework as the principal electronically responsive regions, while the saturated alkyl linker mainly behaves as a conformational spacer. Strong LP(N) → π*(C = O) delocalization of approximately 64–65&#xa0;kcal mol⁻¹ confirms significant amide resonance within the terminal recognition units. Swiss ADME predicts acceptable drug-likeness and high gastrointestinal absorption, but the high TPSA, 13 rotatable bonds, predicted P-glycoprotein substrate status, and possible CYP inhibition indicate permeability, efflux, and metabolic interaction liabilities. Docking against CYP and selected antibacterial, anticancer, and antitubercular targets shows that GA1 can occupy inhibitor-defined binding pockets with Vina scores comparable to reference ligands. The DFT-predicted polar and π-active regions show qualitative agreement with hydrogen-bonding, π-type, and hydrophobic contacts in docked poses. A 100 ns molecular dynamics simulation of the 4KW5–FAD–GA1 complex further supports binding stability, with stable protein backbone RMSD, maintained compactness, persistent protein–ligand hydrogen bonding, and favourable MM/GBSA-estimated binding energy of − 59.71&#xa0;kcal mol⁻¹ dominated by van der Waals interactions. Overall, GA1 is best described as a globally stable but locally interaction-active scaffold, and the present work provides a computational structure–electronics–interaction framework for benzimidazole–diamide systems.</p>

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Integrated computational analysis of electronic, spectroscopic and biomolecular interaction properties of a tetradentate diamide bisbenzimidazole ligand

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  • 发表日期：

    2026年7月9日

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  • Megha Munjal,
  • Gauri Ahuja

摘要

The previously synthesized symmetrical tetradentate bis(benzimidazole) diamide ligand N, N′-bis(1 H-benzimidazol-2-ylmethyl)octanediamide (GA1) was investigated using an integrated DFT, spectroscopic, ADME, molecular docking, molecular dynamics, and MM/GBSA approach to clarify the structure–electronics–recognition features of its benzimidazole–diamide framework. Geometry optimization at the B3LYP-D4/def2-TZVP level reveals an extended pseudo-symmetric conformation stabilized by intramolecular N–H···O hydrogen bonds, with the flexible octanediamide linker separating the two benzimidazole termini and preventing intramolecular π–π stacking. Frontier orbital analysis gives a HOMO–LUMO gap of 5.52 eV, indicating global electronic stability, while M06-2X and ωB97X-D single-point benchmarks confirm that the frontier orbital localization remains concentrated over the benzimidazole/amide regions. NMR and IR spectral comparisons support the optimized geometry and principal functional-group assignments, particularly the amide C = O and benzimidazole/aromatic regions. MESP, Fukui/dual-descriptor, NPA, and NBO analyses consistently identify the amide carbonyl groups, N–H donor sites, and benzimidazole π-framework as the principal electronically responsive regions, while the saturated alkyl linker mainly behaves as a conformational spacer. Strong LP(N) → π*(C = O) delocalization of approximately 64–65 kcal mol⁻¹ confirms significant amide resonance within the terminal recognition units. Swiss ADME predicts acceptable drug-likeness and high gastrointestinal absorption, but the high TPSA, 13 rotatable bonds, predicted P-glycoprotein substrate status, and possible CYP inhibition indicate permeability, efflux, and metabolic interaction liabilities. Docking against CYP and selected antibacterial, anticancer, and antitubercular targets shows that GA1 can occupy inhibitor-defined binding pockets with Vina scores comparable to reference ligands. The DFT-predicted polar and π-active regions show qualitative agreement with hydrogen-bonding, π-type, and hydrophobic contacts in docked poses. A 100 ns molecular dynamics simulation of the 4KW5–FAD–GA1 complex further supports binding stability, with stable protein backbone RMSD, maintained compactness, persistent protein–ligand hydrogen bonding, and favourable MM/GBSA-estimated binding energy of − 59.71 kcal mol⁻¹ dominated by van der Waals interactions. Overall, GA1 is best described as a globally stable but locally interaction-active scaffold, and the present work provides a computational structure–electronics–interaction framework for benzimidazole–diamide systems.