Exploring the Catalytic Nature of Reported Aminoquinazoline‐based <i>Hemophilus influenza N</i>‐acetylglucosamine‐1‐phosphate Uridyltransferase Enzyme Inhibitors by Using In‐Silico Strategies

Inhibiting cell wall biogenesis has proven to be a fruitful strategy for emerging effective antibacterial agents. The bifunctional enzyme N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) is essential for both Gram-positive and Gram-negative bacteria to produce peptidoglycan. The aminoquinazoline inhibitors, 1-10 that were active against Hemophilus influenza GlmU (HiGlmU), extra-precision docking, molecular mechanics-generalized born surface area (MM-GBSA), molecular dynamic (MD) simulation and thermal MMGBSA in-silico strategies were performed in our current research to explore the catalytic behaviour at the binding site. Reported compounds 1-10 occupied the N-terminal domain of the active pocket and showed hydrophobic and hydrogen bonding interactions. We observe that Coulomb and van der Waals binding free energy components are beneficial for the binding of inhibitors. A 150 ns MD simulation of complex 1/HiGlmU was performed in triplicate with different seed numbers which validated our docking protocols. These investigations interested us in designing new molecules. Based on the above findings, we further designed four novel molecules D1-D4, which exhibited high binding affinity to HiGlmU. A 100 ns MD simulation was executed for the D1/HiGlmU complex to explore the catalytic behaviour. Absorption, distribution, metabolism, excretion, and toxicity screening are also performed to predict the drug-likeness. The findings of the currently mentioned investigation may be used in the design and development of potent inhibitors of HiGlmU.