Design and evaluation of novel 1-(5-Isoquinolinesulfonyl) piperazine derivatives as potential Mycobacterium tuberculosis IMPDH Inhibitors: A comprehensive molecular modelling study

The escalating threat of multidrug-resistant Mycobacterium tuberculosis necessitates novel therapeutics targeting essential enzymes like inosine monophosphate dehydrogenase (IMPDH). This study employed integrated computational strategies to design and evaluate new 1-(5-isoquinolinesulfonyl) piperazine derivatives as potent Mtb IMPDH inhibitors. Molecular docking of 33 analogues identified compound 17 as the top hit (MolDock score: -155.094 kcal/mol), guiding the design of optimized analogues. Analogue 17c exhibited enhanced binding (MolDock score: -175.761 kcal/mol). DFT calculations revealed 17c possesses a higher HOMO-LUMO energy gap (3.69 eV) than 17 (3.27 eV), indicating greater stability and reduced electrophilicity (ω = 3.43 eV and 4.36 eV) respectively. Vibrational analysis, supported by Potential Energy Distribution (PED), confirmed the structural stability of compound 17 and its analogue. Furthermore, molecular dynamics simulations conducted over 100 ns revealed superior stability for the IMPDH-17 complex, evidenced by a low average RMSD of 1.6 Å compared to 17c (2.4 Å) and isoniazid (0.5 Å). MM-GBSA calculations quantified this stability, yielding a high binding free energy (ΔG Bind = -54.19 kcal/mol) for 17, primarily driven by van der Waals (-50.37 kcal/mol) and lipophilic (-12.49 kcal/mol) forces. All compounds displayed favourable drug-likeness and ADMET properties. These results posit compound 17 and analogue 17c as highly promising anti-tubercular leads worthy of further experimental investigation.