Discovery of Potent Inhibitors against GTP Pyrophosphokinase of Neisseria meningitidis Serogroup B

Neisseria meningitidis (N. meningitidis) is a non-motile, Gram-negative bacterium. N. meningitidis is often referred as meningococci and causes cerebrospinal fever and bacterial meningitis. Although antibiotics such as penicillin, ciprofloxacin, ceftriaxone, rifampin and polymixin were used to treat bacterial meningitis, but N. meningitidis exhibits multi drug resistance. Therefore, designing novel inhibitors against N. meningitidis would be useful for developing therapies directed towards management of cerebrospinal fever and bacterial meningitis. Genome sequence of N. meningitidis was explored using sRNAPredict tool to identify 249 sRNA candidates of which 68 were enzymes and rests were non enzymes. The enzyme GTP pyrophosphokinase plays a pivotal role in the growth and metabolisms of the pathogen and non-homologous to Homo sapiens, so it was selected as a potential drug target against N. meningitidis. Homology model was built to GTP pyrophosphokinase using Modeller 9v13. Model with lowest DOPE score was selected and validated using PROCHECK, ProSA and ProQ. Published inhibitors such as alpha beta ethylene-ATP, microccin, tetracycline, thiostrepton and viomycin were selected for shape based similarity screening against ASINEX database to generate an in-house library. Docking studies were accomplished using Glide v6.2 for in-house library with GTP pyrophosphokinase which revealed 39 potential leads. Binding free energies (ΔG score) of resulted leads and existing inhibitors were compared to propose five compounds as potent inhibitor of GTP pyrophosphokinase. Lead1 showed lowest ΔG score of -63.65 kcal/mol with strong hydrogen bonding network and with good van der Waals interactions. Five best leads are observed to obey the pharmacological properties at par with 95% of the existing drug molecule. Thus, the lead1 can freezes the functional activity of GTP pyrophosphokinase in the purine metabolism necessary for the replication and DNA repair, to halt proliferation of the of N. meningitidis.