Virtual screening for the identification of novel inhibitors of Mycobacterium tuberculosis cell wall synthesis

BackgroundTuberculosis remains one of the deadliest infectious diseases in humans. It has caused more than 100 million deaths since its discovery in 1882. Currently, more than 5 million people are infected with TB bacterium each year. The cell wall of Mycobacterium tuberculosis plays an important role in maintaining the ability of mycobacteria to survive in a hostile environment. Therefore, we report a virtual screening (VS) study aiming to identify novel inhibitors that simultaneously target RmlB and RmlC, which are two essential enzymes for the synthesis of the cell wall of M. tuberculosis. MethodsA hybrid VS method that combines drug-likeness prediction, pharmacophore modeling and molecular docking studies was used to indentify inhibitors targeting RmlB and RmlC. ResultsThe pharmacophore models HypoB and HypoC of RmlB inhibitors and RmlC inhibitors, respectively, were developed based on ligands complexing with their corresponding receptors. In total, 20 compounds with good absorption, distribution, metabolism, excretion, and toxicity properties were carefully selected using the hybird VS method. DiscussionWe have established a hybrid VS method to discover novel inhibitors with new scaffolds. The molecular interactions of the selected potential inhibitors with the active-site residues are discussed in detail. These compounds will be further evaluated using biological activity assays and deserve consideration for further structure-activity relationship studies. A virtual screening workflow has been established for retrieving novel inhibitors targeting RmlB and RmlC simultaneously. Display Omitted 3D structure of Mycobacterium tuberculosis RmlB (mtRmlB) was built by homology modeling.Pharmacophore models of RmlB inhibitors and RmlC inhibitors were built based on the ligand-receptor complexes.A hybrid virtual screening approach based on drug-likeness prediction, pharmacophore and molecular docking was performed for retrieving novel inhibitors targeting RmlB and RmlC simultaneously.