Identification of novel potential atibiotic for tuberculosis by in silico structure-based drug screening
Yuya Izumizono

Abstract Enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis (MTB) is a key enzyme of the typeⅡfatty acid synthesis involved in the production of mycolic acid and is known as a target protein for isoniazid, an effective antibiotic for tuberculosis(TB). The increasing prevalence of TB in many areas of the world, associated with the rise in drug-resistant MTB strains, presents a major threat to global health. In this study, we attempted to identify novel antibiotics specifically targeting MTB enoyl-acyl carrier protein reductase. We performed in silico structure-based drug screening using crystal structure data of MTB enoyl-acyl carrier protein reductase (PDB code; 2H7I) and the virtual compound library, which includes 152,102 chemicals. By a two-step virtual screening method using DOCK (first screening) and GOLD (second screening), we identified 5 compounds expected to have high binding affinity to an active center of MTB enoyl-acyl carrier protein reductase. Moreover, we verified that these compounds have antibiotic effects for model bacterial strains, Mycobacterium vanbaalenii and Rhodococcuss opacus, by in vitro experiment. The chemical compound is likely useful for the research and development of new antibiotic for TB.

Fig. enoyl-acyl carrier protein reductase active center pocket