Identification of a novel class of small compounds with anti-tuberculosis activity by in silico structure-based drug screening

Abstract

The enzymes responsible for biotin biosynthesis in mycobacteria have been considered as potential drug targets owing to the important role in infection and cell survival that the biotin synthetic pathway plays in Mycobacterium tuberculosis. Among the enzymes that comprise mycobacterium biotin biosynthesis systems, 7,8-diaminopelargonic acid synthase (DAPAS) plays an essential role during the stationary phase in bacterial growth. In this study, compounds that inhibit mycobacterial DAPAS were screened in the virtual chemical library using an in silico structure-based drug screening (SBDS) technique, and the antimycobacterial activity of the selected compounds was validated experimentally. The DOCK-GOLD programs utilized by in silico SBDS facilitated the identification of a compound, referred to as KMD6, with potent inhibitory effects on the growth of model mycobacteria (M. smegmatis). The subsequent compound search, which was based on the structural features of KMD6, resulted in identification of three additional active compounds, designated as KMDs3, KMDs9 and KMDs10. The inhibitory effect of these compounds was comparable to that of isoniazid, which is a first-line antituberculosis drug. The high antimycobacterial activity of KMD6, KMDs9 and KMDs10 was maintained on the experiment with M. tuberculosis. Of the active compounds identified, KMDs9 would be a promising pharmacophore, owing to its long-term antimycobacterial effect and lack of cytotoxicity.

Computational Screening and Experimental Validation of Inhibitor Targeting the Complex Formation of Grb14 and Insulin Receptor

“…First, in silico SBDS was performed to search for compounds that interfere with the PPI between the IRβ and Grb14 (BPS). In general, the removal of the inhibitor structure from the protein–inhibitor complex provides a favorable binding pocket when identifying competitive inhibitors through in silico SBDS [ 19 ]. Herein, two binding pockets, shown as groove A and B, respectively, were identified after removal of the Grb14 (BPS) structure from 2AUH ( Figure 1 A).…”

“…Preparation of the virtual chemical library composed of 154,118 compounds was reported previously [ 19 ]. Structural data of the IRβ in complex with the Grb14 (BPS) region (PDB-id: 2AUH) were used after removal of the BPS region structure.…”

“…Molecules 2024, 29, x FOR PEER REVIEW 3 of 11 from the protein-inhibitor complex provides a favorable binding pocket when identifying competitive inhibitors through in silico SBDS [19]. Herein, two binding pockets, shown as groove A and B, respectively, were identified after removal of the Grb14 (BPS) structure from 2AUH (Figure 1A).…”

Computational Screening and Experimental Validation of Inhibitor Targeting the Complex Formation of Grb14 and Insulin Receptor

“…First, in silico SBDS was performed to search for compounds that interfere with the PPI between the IRβ and Grb14 (BPS). In general, the removal of the inhibitor structure from the protein-inhibitor complex provides a favorable binding pocket when identifying competitive inhibitors through in silico SBDS [19]. Herein, two binding pockets, shown as groove A and B, respectively, were identified after removal of the Grb14 (BPS) structure from 2AUH (Figure 1A).…”