In Silico Approach: Anti-Tuberculosis Activity of Caespitate in the H37Rv Strain

Abstract

Tuberculosis is a highly lethal bacterial disease worldwide caused by Mycobacterium tuberculosis (Mtb). Caespitate is a phytochemical isolated from Helichrysum caespititium, a plant used in African traditional medicine that shows anti-tubercular activity, but its mode of action remains unknown. It is suggested that there are four potential targets in Mtb, specifically in the H37Rv strain: InhA, MabA, and UGM, enzymes involved in the formation of Mtb's cell wall, and PanK, which plays a role in cell growth. Two caespitate conformational structures from DFT conformational analysis in the gas phase (GC) and in solution with DMSO (CS) were selected. Molecular docking calculations, MM/GBSA analysis, and ADME parameter evaluations were performed. The docking results suggest that CS is the preferred caespitate conformation when interacting with PanK and UGM. In both cases, the two intramolecular hydrogen bonds characteristic of caespitate's molecular structure were maintained to achieve the most stable complexes. The MM/GBSA study confirmed that PanK/caespitate and UGM/caespitate were the most stable complexes. Caespitate showed favorable pharmacokinetic characteristics, suggesting rapid absorption, permeability, and high bioavailability. Additionally, it is proposed that caespitate may exhibit antibacterial and antimonial activity. This research lays the foundation for the design of anti-tuberculosis drugs from natural sources, especially by identifying potential drug targets in Mtb.

Keywords: H37Rv strain; MM/GBSA; antituberculosis activity; caespitate; molecular docking.

Figure 1

Intramolecular hydrogen bonds (highlighted with green lines) identified in the optimized molecular structure of the caespitate conformers used in this work. (A) CG, extended conformation preferred in the gas phase. The two IHBs identified in the global minimum are formed by the O12−H13⋯O15 atoms and by the O8H9⋯O41 atoms. (B) CS, hairpin conformation favored in the DMSO solution phase. Similar to the CG conformation, two IHBs identified in the global minimum are formed by the O10−H11⋯O15 atoms and by the O12−H13⋯O41 atoms.

Scheme 1

Chemical reactions catalyzed by the four enzymes proposed with distinct localization: those involving the InhA and MabA enzymes take place within the cell wall of Mtb, specifically in the mycolic acids (highlighted with red and blue arrows), while the reaction catalyzed by UGM is situated in the arabinogalactans (highlighted with a green arrow). Additionally, the reaction mediated by PanK contributes to the bacterium’s growth process (highlighted with a yellow arrow).

Figure 2

(A) Graphical 3D representation of the main interactions in the UGM–CS complex after semiflexible docking simulation in Glide. (B) Graphical 3D representation of the main interactions in the UGM–CS complex after semiflexible docking simulation in AutoDock Vina.

Figure 3

(A) Graphical 3D representation of the main interactions in the PanK–CS complex after semiflexible docking simulation in Glide. (B) Graphical 3D representation of the main interactions in the PanK–CS complex after semiflexible docking simulation in AutoDock Vina.

Figure 4

(A) Graphical 3D representation of the main interactions in the MabA–CS complex after semiflexible docking simulation in Glide. (B) Graphical 3D representation of the main interactions in the MabA–CS complex after semiflexible docking simulation in AutoDock Vina.

Figure 5

(A) Graphical 3D representation of the main interactions in the InhA–CS complex after semiflexible docking simulation in Glide. (B) Graphical 3D representation of the main interactions in the InhA–CS complex after semiflexible docking simulation in AutoDock Vina.

Figure 6

Graphical 3D representation of the initial complex models with the complexes obtained in Vina and Glide. (A) UGM enzyme; (B) PanK enzyme; (C) MabA enzyme; and (D) InhA enzyme.