A comparative QSAR analysis, 3D-QSAR, molecular docking and molecular design of iminoguanidine-based inhibitors of HemO: A rational approach to antibacterial drug design

Abstract

QSAR models of 25 iminoguanidine derivatives with inhibitory HemO were developed. The QSAR model was built by using DFT-MLR and the best QSAR model has R2, Q2 values of 0.6569 and 0.5493 for cross-validated and non-cross-validated. The predictive ability of QSAR model was further validated by a test set of 7 compounds, giving R2pred value of 0.7123. 3D-QSAR and docking studies were used to find the actual conformations of chemicals in active site of HemO, as well as the binding mode pattern to the binding site in HemO enzyme. Molecular dynamics and simulations study revealed that A-chain of HemO protein was stable at and above 100ps with respect to temperature (at and above 298 K), electrostatic (at and above 57500 kJ/mol), kinetic energy (at and above 12200 kJ/mol) and total energy (at and above 30500 kJ/mol). The information provided by QSAR, 3D-QSAR and molecular docking may provide a better understanding of the structural requirements of iminoguanidine-based inhibitors of HemO and help to design potential antibacterial molecules. Four (4) new compounds (4A, 5A, 6A, and 7A) with high predicted antibacterial activities have been theoretically designed and they are expected to be confirmed experimentally.