Virtual high screening throughput and design of 14
-lanosterol demethylase inhibitors against <i>Mycobacterium tuberculosis</i>

Abstract

The current treatment against Mycobacterium tuberculosis, the causative agent of tuberculosis in humans, requires a drug combination and the last two decades have passed without significant development of novel chemicals for the treatment of tuberculosis. The elucidation of
the sequence of genomes for M. tuberculosis has identified a gene that encodes a protein with 34% amino acid sequence similarity to human CYP51 which is referred to as MT CYP51. Azole compounds which inhibit fungal CYP51, also inhibited the growth of Mycobacterium bovis and Mycobacterium smegmatis, at nanomolar concentration. In this study, over 10,000 ligands from the NCI database were virtually screened for their free binding energy against mycobacterial
14-lanosterol demethylase by docking. Ten hits which bound the enzyme at lowest free energy ranging from -13 to -14.5 Kcal/mol where selected. Various fragments from selected ligands were incorporated together to generate new lead compounds that bind the enzyme at the energy three times lower than fluconazole. To prove the concept, literature search on the inhibitory concentration at 90% (IC90) demonstrated that ligands which were selected had activity against
the M. tuberculosis which correlated well with binding free energy with few exceptions.