In Silico Screening, Ligand-Efficiency Analysis and Pharmacokinetic Profiling of Ocimum gratissimum Phytochemicals Targeting the AcrB Multidrug Efflux Pump

Overexpression of the AcrAB-TolC efflux pump in Escherichia coli drives clinically challenging multidrug resistance, necessitating novel resistance-modifying adjuvants. In this study, an in silico pipeline integrating Glide molecular docking, ADMETlab 3.0 profiling, oral bioavailability modeling, and bioactivity analysis was deployed to evaluate 229 Ocimum gratissimum phytochemicals against the distal binding pocket of the AcrB tight protomer (PDB ID: 4DX5). Glide extra-precision (XP) docking identified high-affinity hits, including ocimol (−10.71 kcal/mol), menthyl chavicol (−8.49 kcal/mol), bulnesol (−7.40 kcal/mol), cubebol (−7.34 kcal/mol), and zizanene (−6.91 kcal/mol), alongside reference antibiotics ciprofloxacin (−10.19 kcal/mol) and meropenem (−7.28 kcal/mol). Binding interaction analyses revealed that ocimol anchors the polar switch loop via an Asn274 hydrogen bond while spanning the hydrophobic pocket. Conversely, the selected sesquiterpenoids embed within the aromatic 'phenylalanine trap' (Phe136, Phe178, Phe610, Phe615, Phe617, and Phe628), suggesting potential steric interference with substrate extrusion pathways. Multi-parameter developability filtering demonstrated that although ocimol achieved the highest docking score, it displayed two Lipinski violations, poor aqueous solubility (ESOL logS = −6.45), and an unfavorable lipophilicity penalty (LELP = 29.18). In contrast, zizanene emerged as the most balanced lead candidate, exhibiting zero Lipinski and PAINS liabilities, balanced solubility (ESOL logS = −3.85), robust ligand efficiency (LE = 0.461 kcal/mol/HA), favorable lipophilic efficiency (LELP = 8.89), and low predicted toxicity. These computational predictions highlight zizanene as a promising computationally prioritized scaffold for further investigation as a potential AcrB-targeting resistance-modifying adjuvant, warranting downstream experimental validation.