Lead generation of UPPS inhibitors targeting MRSA: Using 3D- QSAR pharmacophore modeling, virtual screening, molecular docking, and molecular dynamic simulations

Abstract

Abstract Due to the threat of emerging antibiotic resistance, the quest for new antibacterial agents remains an essential endeavor in drug discovery. Bacterial resistance can be combated by using inhibitors that work on a different mechanism than current antibiotics thus avoiding cross-resistance by targeting new enzymes in the same pathway. Undecaprenyl Pyrophosphate Synthase (UPPS) is a vital target enzyme located in the very early steps of bacterial cell wall biosynthesis. UPPS inhibitors were found to have anti-bacterial activity on resistant strains such as MRSA and VRE when used alone or in combination with current agents. We used several consecutive computer-based protocols to identify novel UPPS inhibitors. The 3D QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery studio 4.1 was adopted to generate a valid predictive pharmacophore model utilizing a set of UPPS inhibitors with known reported activity. The generated model consists of four features: one Hydrogen Bond Acceptor (HBA), two Hydrophobic (HYD), and one Ring Aromatic (RA). It had a correlation coefficient of 0.86 and a null cost difference of 191.39 reflecting its high predictive power. Hypo1 was proven statistically significant using Fischer's randomization at 95% confidence level. The validated pharmacophore model was used for the virtual screening of several databases (ZINC15 library, drug-like Diverse, Mini Maybridge, and scPDB). The resulting hits were filtered using SMART and Lipinski's filters. The hits were docked into the binding site of the UPPS protein (PDB ID: 5KH5) affording 70 hits with higher docking affinities than the reference compound (6TC, − 21.17 Kcal/mol). The top five hits were eventually elected through extensive docking analysis and visual inspection based on docking affinities, fit values, and key residue interactions with the UPPS receptor. Molecular dynamic simulations of the top five hit-protein complexes were performed using Discovery Studio (DS) to confirm the stability of the protein-ligand complexes. As a result, these promising five hit molecules may be considered as promising novel UPPS inhibitors.