Structure-Based Drug Design for Tuberculosis

Structure-based drug design (SBDD) is one of the advanced techniques of computeraided drug design used to expedite the drug discovery process. Tuberculosis (TB) is one of the therapeutic areas where the discovery of novel therapeutics—and the use of existing therapeutics—is still challenging due to microbial drug resistance (MDR). SBDD techniques are being utilized to exploit various therapeutically viable anti-TB targets to obtain novel scaffolds, such as RNA polymerase, enoyl-acyl protein reductase, DprEl, DprE2, MmpL3, MmpL7, QcrB, topoisomerase II complex (DNA gyrase), EmbC [arabinogalactan (AG) and lipoarabinomannan (LAM)], EthR2, F-ATP synthase, ketomycolic acid, and methoxy mycolic acid synthesis. The inspiring journey of the life-saving anti-TB drug Bedaquiline (TMC207) against MDR TB began with the screening of a 70,000-compound library against the F-ATP synthase of a non-pathogenic TB strain, followed by subsequent SBDD efforts. Moreover, the nitroimidazole derivatives Delamanid and Pretomanid were discovered through scaffold modification and high-throughput screening. The benzothiazinone derivative Macozinone was discovered through a lead optimization campaign targeting DprEl inhibitors. Several successful SBDD studies have been reported in recent years, facilitating the discovery of novel anti-TB agents. In this chapter, SBDD approaches are discussed in connection with the discovery and optimization of anti-TB drugs.