article · Scientific African
Tuberculosis caused by multidrug-resistant strains requires new treatments targeting vital bacterial enzymes such as inosine monophosphate dehydrogenase. To address this, integrated computational modelling was used to design and evaluate novel 1-(5-isoquinolinesulfonyl) piperazine derivatives. Initial docking across 33 analogues identified compound 17 as a leading candidate, which then guided the design of further optimised molecules, notably analogue 17c. Density functional theory calculations showed that 17c possesses greater electronic stability and lower electrophilicity compared to compound 17. Structural stability was further supported by vibrational analysis. During 100-nanosecond molecular dynamics simulations, the complex formed by compound 17 and the target enzyme demonstrated high structural stability and strong binding free energy driven by van der Waals and lipophilic interactions. Across the evaluated compounds, favourable drug-likeness and pharmacokinetic profiles were observed, identifying these molecules as candidates for physical laboratory testing.
Rising antibiotic resistance makes standard tuberculosis therapies less effective. Identifying new chemical compounds that attack critical bacterial enzymes offers a path toward fresh treatment options. Using computer simulations to design and test candidate molecules helps researchers pinpoint the most stable and effective drug candidates before committing time and funding to costly laboratory synthesis.
This research provides computational lead candidates for pharmaceutical developers and drug discovery programmes working on anti-tubercular therapeutics. The work represents very early-stage discovery based entirely on in silico modelling. Real-world application will require chemical synthesis followed by in vitro enzymatic testing, cellular assays, and subsequent preclinical development to validate the therapeutic potential of the identified compounds.
AI-generated from the published abstract. Always read the original work before citing.
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 .
This page summarises published work. The authoritative version sits with the publisher.
DOI: 10.1016/j.sciaf.2025.e03043
Is something wrong with this record? Report it or request removal.
Discussion
Have you built on this work, tried to replicate it, or seen it applied in practice? Share what you know. Verified researchers and MARATTO™ domain experts can open a discussion, and any member can reply. Contributions are reviewed before they appear.
No discussion yet. Open the first thread.
New to MARATTO™? Create a free account.
