Virtual Screening of Compounds Against Mycobacterium tuberculosis Maltosyltransferase GlgE

The prevalence of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) particularly the occurrence of multi-drug resistant and extensively-drug resistant strains of Mtb has prompted intense efforts to develop new anti-TB drugs. The enzyme maltosyltransferase GlgE of M. tuberculosis was determined to be a potential drug target. In this work, homology model of Mtb maltosyltransferase GlgE was generated based on eight reported protein structures with similar amino acid sequence. A pharmacophore based on the model was used to screen two databases of natural products. The virtual screening top hit, F_2.726 with binding energy (BE) of -322.83 kcal/mol, and the natural substrate maltose (BE = -322.85 kcal/mol), have comparable binding affinity. The top hit, a phenylcyclohexenyl carbamimidic acid, was then subjected to in silico structure optimization by De Novo Evolution method and yielded five variants with better binding affinities. The study also indicates that the GlgE structures from Streptomyces coelicolor can be used as syltransferase GlgE [7]. The inhibition of GlgE does not only lead to failure of biosynthesis of -glucan, the main constituent of the mycobacterial capsule that is thought to be involved in immune evasion and virulence, but also the toxic accumulation of maltose-1-phosphate, that eventually leads to cell death