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[Article]
 

Abstract.
Structures of 12 structurally unrelated agents (training set) and 19 diverse agents (prediction set) were modeled at the PM3 level and the molecular descriptors obtained were correlated with pMIC (pMIC=-log(MIC/mol/dm³) values for E. coli strains KAM32 (without VmrA efflux pump) and KAM32/pVCJ6 (with VmrA). Partial Least Squares (PLS) and Principal Component Regression (PCR) models were built and used to predict pMICs. Hierarchical Cluster Analysis (HCA) and Principal Component Analysis (PCA) were performed for training and training+prediction sets. Agent-receptor interaction descriptors were calculated for complexes with these or the most similar agents, as retrieved from the Protein Data Bank (PDB). Good substrates of VmrA from Vibrio parahaemolyticus AQ3334 are nonlinear, rigid, and condensed heteroaromatics, rather hydrophobic, involved in aromatic-aromatic, hydrophobic-hydrophobic, hydrophobic-hydrophilic, and hydrogen bond contacts with VmrA. Qualitative and quantitative structure-activity relationships [(Q)SARs] predicted well the resistance/sensitivity of VmrA to 19 agents. This can have practical application in assays with V. parahaemolyticus and other noncholera Vibrio spp. Agent-receptor interaction descriptors correlate with experimental and predicted pMICs, giving a new insight into possible VmrA-mediated agent efflux mechanisms.

Keywords.
Activity-Structure Relationships; ATP-Binding Cassette Efflux Pump; Chemometrics; Cytochrome P450 Sterol 14a-Demethylase; Quantitative Genome/Structure-Activity Relationship.

Keywords Plus.