Exploring the Natural Products Atlas (NPAtlas) Database for Hunting Prospective Irreversible Covalent DprE1...

As the second most deadly infectious disease worldwide after COVID-19, tuberculosis (TB) remains a pressing global health issue, further aggravated by multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. There is an urgent need to identify new anti-TB treatments and novel therapeutics to confront drug resistance. The decaprenylphosphoryl-D-ribose oxidase (DprE1) is an essential protein for the biosynthesis of the mycobacterial cell wall, and its inhibition features a promising antitubercular strategy. NPAtlas was utilized as a reference database, comprising natural products with confirmed biological effects. The aim of the current study is to identify and prioritize promising nitro-containing natural products from the NPAtlas as potential covalent DprE1 inhibitors using advanced in silico approaches. Herein, the docking scores of 133 nitro-containing NPAtlas compounds were assessed using a covalent docking technique. Thereafter, NPAtlas compounds with docking scores lower than PBTZ169 (calc. -7.8 kcal·mol^-1) were subjected to molecular dynamics simulation (MDS), accompanied by binding energy estimations utilizing the MM-GBSA approach. Based on MM-GBSA//250 ns MDS, NPA011203, NPA013234, NPA016048, NPA012944, NPA001712, and NPA002823 demonstrated higher binding affinities against DprE1 with ΔG _binding values of -75.6, -62.7, -61.6, -57.6, -54.8, and -50.7 kcal·mol^-1, respectively, than PBTZ169 (calc. -49.4 kcal·mol^-1). The identified NPAtlas compounds also demonstrated structural and energetic stability within the DprE1 active site throughout 250 ns MDS. Physicochemical and ADMET predictions of the identified NPAtlas compounds indicated a suitable molecular size, favorable absorption, and negligible toxicity, suggesting their potential oral bioavailability. These in silico outcomes provide preliminary insights into the identified NPAtlas compounds as potential DprE1 inhibitors and can guide subsequent in vitro/in vivo experiments.