Design of benzofuro [3,2-d] pyrimidine-based MmpL3 inhibitors as potential anti-tuberculosis agents using integrated...

The continued emergence of drug resistant Mycobacterium tuberculosis highlights the pressing need for novel therapeutic strategies targeting essential and underexploited bacterial pathways. In this study, an integrated in silico approaches was employed to rationally design benzofuro [3,2-d] pyrimidine-based inhibitors targeting mycobacterial membrane protein Large 3 (MmpL3), a key transporter involved in mycolic acid biosynthesis. A structure-based e-pharmacophore model comprising six energetically significant features was developed from the MmpL3 crystal structure (PDB ID: 7C2M) and used to screen a curated ChEMBL dataset, reducing 5752 compounds to 278 candidates. Subsequent QSAR modeling demonstrated robust predictive performance (R2 = 0.65, Q2 = 0.63), enabling activity-guided prioritization. Hierarchical molecular docking and MM-GBSA calculations identified three lead compounds (D3, D12, and D16) with enhanced binding affinities (ΔG_bind =  - 50.96- - 56.36 kcal/mol) relative to the reference ligand (- 49.85 kcal/mol). Molecular dynamics simulations over 200 ns confirmed the structural stability of the MmpL3-ligand complexes, with backbone RMSD values stabilizing below 2.6 Å and persistent hydrogen bonding within the binding cavity. ADMET profiling indicated favorable oral bioavailability and acceptable drug-likeness. Collectively, these findings highlight benzofuro[3,2-d]pyrimidine scaffolds as promising leads for MmpL3-targeted anti-tuberculosis drug development.

The online version contains supplementary material available at 10.1007/s40203-026-00646-z.