Computational modeling of the DprE1 and DprE2 protein interface for antitubercular drug discovery

Tuberculosis (TB) remains a major global health threat, with rising cases of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains compromising current treatment strategies. These challenges highlight the urgent need to identify novel therapeutic targets. The DprE1/DprE2 enzyme complex in Mycobacterium tuberculosis, essential for arabinogalactan biosynthesis in the mycobacterial cell wall, represents a promising alternative target. Inhibiting this complex can disrupt cell wall integrity, offering a novel mechanism of action that may overcome resistance associated with current drugs. In this work, we performed protein-protein docking of DprE1and DprE2 proteins to establish the DprE1/DprE2 complex. The generated protein complex was then validated through MD simulation and substrate binding analysis. It was found that a protein interface site was necessary for the transfer of DPX from DprE1to DprE2 to further biotransformation into DPA. The hypothesis was to inhibit this substrate binding at the interface, and also a potential inhibition of DprE1/DprE2 complex formation through an external ligand binding. The Asinex screening database was virtually screened at the interface. The top docked molecule (Asinex compound ID-64519) was selected from the result to analyze their binding interaction analysis, docking score and MD simulation. The ligand shows comparable binding free energy at the interface site with the substrate (DPX), and comparable MM-GBSA and MM-PBSA score. Further, the per-residue decomposition analysis helped us to identify the hot spot and key residues. This finding suggests the possible inhibition of Mtb cell wall synthesis through substrate binding inhibition at the protein interface.