The Chemical Property Position of Bedaquiline Construed by a Chemical Global Positioning System-Natural Product

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.

Keywords: ChemGPS-NP; antituberculosis agents; bedaquiline; chemical property space; data mining; screening; structural similarity.

Figure 1

Chemical structures of bedaquiline and different typical antituberculosis quinoline compounds.

Figure 2

Position of bedaquiline (large pink sphere), the 100 closest antituberculosis compounds (small spheres), and quinoline compounds (green spheres), using ChemGPS-NP scores, where PC1 (x = red), PC2 (y = yellow), and PC3 (green).

Figure 3

Three sets of 50 antituberculosis compounds classified as closest to bedaquiline (large pink sphere): ChemGPS-NP (pink), Tanimoto ecfp (turquoise), and Tanimoto maccos (orange), projected on a three-dimension space.

Figure 4

Red and green speckles represent mycobacterium permeability and impermeability, respectively. The large pink sphere represents the bedaquiline position in the chemical property space constructed by ChemGPS-NP for natural compounds.