Three-Dimensional (3D) pharmacophore-based identification of possible ATP-synthase inhibitors for mycobacterium tuberculosis (Mtb)
Tuberculosis (TB) is defined as a chronic infectious disease caused by the air-borne transmission of Mycobacterium tuberculosis (Mtb). Due to high prevalence of Mtb in South Africa, it is classified as a high burden country by the World Health Organization (WHO). Multi-drug resistant TB (MDR-TB) strains display a resistance to both Isoniazid and Rifampicin, while extensively drug resistant (XDR-TB) includes resistance to fluoroquinolone as well as other second- line drugs (Capreomycin, Kanamycin and Amikacin). Bedaquiline (BDQ) is a diarylquinoline aimed at inhibiting the adenosine triphosphate (ATP) synthase of MDR-TB, thereby targeting the energy metabolism mechanism of Mtb. Drug regimens utilized prior to BDQ have shown low success rates in patients with XDR-TB. The technologies of computer-aided drug discovery (CADD) has proven to be a powerful tool in reducing costs, as well as time, and ensures the efficiency of lead compound identification. CADD can be divided into two categories; structure-based (SB) and ligand-based (LB) drug discovery. The categories are employed are based on the input data; in this study the LB method was employed as the known descriptors were found to inhibit Mtb ATP-synthase. These descriptors (ligands) were then used to generate pharmacophore models of varying quality and features. A pharmacophore model is a set of features that a ligand requires to be recognized by the drug target, Mtb ATP-synthase.
Mycobacterium Tuberculosis, First-line drugs, Virtual Screening, ATP-synthase, Multi-drug Resistance
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