Exploring spirocyclic isoquinoline-piperidine compounds in tuberculosis therapy: ADMET profiling, docking, DFT, MD simulations, and MMGBSA analysis

Tuberculosis remains a global health challenge due to drug-resistant strains. MmpL3 inhibitors have emerged as promising anti-tubercular agents, and their clinical development has been hindered by poor microsomal stability. This study computationally designed and screened 40 spirocyclic analogs, and compared them with ICA38 and SQ109. In silico analyses, including docking, MD simulations, and DFT calculations, were conducted to assess their potential as anti-tubercular agents, highlighting promising candidates for further development. Docking studies using Glide software identified C21 (3,4- dichloro derivative) and C20 (5-chloro derivative) as promising candidates, exhibiting binding scores of −9.79 kcal/mol and −9.64 kcal/mol, respectively. Both compounds interacted with the active site residue Asp645 via hydrogen bonding and also formed a hydrophobic interaction. DFT results revealed that C21 displayed the balanced chemical reactivity, characterized by high dipole moment (3.63D), an optimal energy gap (0.18752 eV), softness and hardness (η = 0.09376 eV, σ = 10.666 eV⁻¹), high electron affinity (0.02305 eV), high electronegativity (0.11681 eV) and high ionization potential (0.21057 cV). On the other hand, C20 exhibited similar electronic properties with marginal differences than C21. MD simulations showed C21 and C20's stability (RMSD 2.4 Å and 2.2 Å, RMSF <2.5 Å), indicating improved Arg344-Leu354 stability. Additionally, C21 and C20 maintained Asp645 interactions (91 %, 97 %) and showed strong binding with free energy values (MMGBSA: −72.23, −66.50 kcal/mol). These findings highlight the efficiency of the compounds C21 and C20 with strong binding affinity, favorable stability, and optimal electronic properties, making them promising candidates for further development of next-generation MmpL3 inhibitors.