Electronic and Lipophilicity-Guided Optimization of Cyclopentanone Derivatives: A Combined DFT and Molecular Docking Investigation Targeting the 1KZN Protein

Abstract

The rational modulation of electronic structure combined with lipophilicity optimization constitutes represents a fundamental strategy in modern drug design. In this study, four systematically substituted cyclopentanone derivatives (H, OMe, F, NO₂) were studied through a density functional theory (DFT) calculations and molecular docking simulations against the Escherichia coli 24 kDa domain in complex with clorobiocin (PDB ID: 1KZN). Frontier molecular orbital energies, HOMO–LUMO energy gaps (ΔE), dipole moments, and Mulliken charge distributions were analyzed to elucidate substituent-induced electronic modulation.

Docking simulations revealed stable binding conformations (RMSD < 2 Å) with binding affinities ranking as: NO₂ > OMe > F > H. The nitro-substituted derivative displayed the smallest energy gap, ΔE (8.071 eV), the lowest and most stabilized LUMO energy (−1.734 eV), and enhanced carbonyl charge localization, correlating with the strongest docking score (−6.6872 kcal/mol).

Statistical analysis demonstrated that reduced energy gaps and enhanced electrophilicity significantly improve ligand–protein interactions. Collectively. These findings establish a mechanistic electronic–affinity relationship for optimizing cyclopentanone-based pharmacophores and support electron-withdrawing substitution as a promising strategy for enhancing binding affinity against antibacterial targets.