Virtual Screening On Pantothenate Synthetase From Mycobacterium Tuberculosis

Tuberculosis (TB) is an infectious disease caused by the pathogenMycobacterium tuberculosis (MTB), which generally evades the host immune systemand drug regime by entering dormant phase within macrophage. At present, clinicallyused antibiotics target very few essential functions of mycobacterium and do not meetthe huge demand for the treatment of patients with TB. An increase in the prevalenceof drug-resistant strains of MTB in the past decades has renewed focus on thedevelopment of new drugs that can treat drug-sensitive, drug-resistant and persistentTB infections. With the development of structural biology and the availability of thegenome sequence of MTB, it may provide promising opportunities for us to establishnew targets and thus serve as starting point for rational designing of novel drugs. As aresult, many anti-TB compounds have been discovered by means of virtual screeningon newly established targets, especially in the field of enzyme class. In this study,virtual screening has been performed on pantothenate synthetase (PS) which isresponsible for the synthesis of pantothenate, an essential precursor for thebiosynthesis of coenzyme A (CoA) and acyl carrier proteins (ACP). Because theenzyme is not present in humans and both CoA and ACP are essential cofactors formycobacterial growth, MTB-PS is a potential target for new anti-TB drugdevelopment. In this thesis, we employ docking program Glide and Specs database toscreen MTB-PS and then select33potential hits according to specific interactionsbetween ligands and MTB-PS, ADMET and drug-like properties. This study providessome novel potential hits against MTB-PS through virtual screening, andexperimental tests and lead optimization are underway with the hope to find newanti-TB drugs with novel mechanisms of action.