Abstract
Bedaquiline is a novel adenosine triphosphate synthase inhibitor anti-tuberculosis drug. Bedaquiline belongs to the class of diarylquinolines, which are antituberculosis drugs that are quite different mechanistically from quinolines and flouroquinolines. The fact that relatively similar chemical drugs produce different mechanisms of action is still not widely understood. To enhance discrimination in favor of bedaquiline, a new approach using eight-score principal component analysis (PCA), provided by a ChemGPS-NP model, is proposed. PCA scores were calculated based on 35 + 1 different physicochemical properties and demonstrated clear differences when compared with other quinolines. The ChemGPS-NP model provided an exceptional 100 compounds nearest to bedaquiline from antituberculosis screening sets (with a cumulative Euclidian distance of 196.83), compared with the different 2Dsimilarity provided by Tanimoto methods (extended connective fingerprints and the Molecular ACCess System, showing 30% and 182% increases in cumulative Euclidian distance, respectively). Potentially similar compounds from publicly available antituberculosis compounds and Maybridge sets, based on bedaquiline’s eight-dimensional similarity and different filtrations, were identified too.
Highlights
Bedaquiline was discovered at JanssenPharmaceutica and designated as an orphan medicinal product
Bedaquiline has proved to be a potent agent against M. tuberculosis H37Rv with an MIC equal to 0.03 mg/mL
Bedaquiline has demonstrated efficacy against resistant M. tuberculosis strains and activity against dormant mycobacteria [1], which have been reported as having infected over two billion human beings [2]
Summary
Bedaquiline (trade name Sirturo, code name TMC207) was discovered at JanssenPharmaceutica and designated as an orphan medicinal product. Bedaquiline (trade name Sirturo, code name TMC207) was discovered at Janssen. Bedaquiline has proved to be a potent agent against M. tuberculosis H37Rv with an MIC equal to 0.03 mg/mL and against a range of M. tuberculosis clinical isolates with an MIC up to 0.12 mg/mL. Bedaquiline has demonstrated efficacy against resistant M. tuberculosis strains and activity against dormant mycobacteria [1], which have been reported as having infected over two billion human beings [2]. The mechanism of action of the diarylquinoline class of drugs was anticipated by comparing the genomic sequences of mutant resistant strains of M. tuberculosis and M. smegmatis to those that were susceptible to bedaquiline. The compound did not inhibit gyrase activity when tested against the purified enzyme, indicating that this molecule does not share mechanism of action with quinolones [3]
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