Novel Chemical Compounds Based on 1,2,3-Triazoles as Potential Mycobacterium Tuberculosis Inhibitors. In-silico Study through Pharmacophore Modeling, Molecular Docking, Molecular Dynamics, and ADMET Predictions
نویسندگان
1 Molecular Chemistry and Natural Substances Laboratory (MCNSL), Faculty of Science, Moulay Ismail University, Meknes, Morocco
2 Molecular Chemistry and Natural Substances Laboratory (MCNSL), Faculty of Science, Moulay Ismail University, Meknes, Morocco
3 Molecular Chemistry and Natural Substances Laboratory (MCNSL), Faculty of Science, Moulay Ismail University, Meknes, Morocco
4 Molecular Chemistry and Natural Substances Laboratory (MCNSL), Faculty of Science, Moulay Ismail University, Meknes, Morocco
5 Molecular Chemistry and Natural Substances Laboratory (MCNSL), Faculty of Science, Moulay Ismail University, Meknes, Morocco
6 Molecular Chemistry and Natural Substances Laboratory (MCNSL), Faculty of Science, Moulay Ismail University, Meknes, Morocco
doi
10.22036/pcr.2024.449578.2507چکیده
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a significant infectious disease that primarily affects the lungs and can spread throughout the body. The emergence of multidrug-resistant and totally drug-resistant strains of M. tuberculosis presents a major challenge in eradicating TB, necessitating the development of novel anti-tubercular drugs. This study focuses on the analysis of 34 analogues of 1,2,3-triazoles, which are chemical compounds with potential in tuberculosis drug design. A pharmacophore model was constructed based on structural and functional information from active compounds. The atom-based 3D-QSAR pharmacophore model utilized a five-point hypothesis (ARRR.4) to elucidate the compounds' biological activity, yielding high values for (R^2=0.9613, Q^2=0.7310). By utilizing the generated 3D contour maps, four new compounds were designed, and their ADME/Tox properties were predicted. The results indicate that these compounds possess potent pharmacological characteristics. Furthermore, molecular anchoring analysis revealed that compounds A1-A4 exhibited higher anchoring scores (-9.6, 9.5, 9.4, and 9.4 kcal/mol, respectively) compared to compound 31. This signifies significant hydrogen bonding and hydrophobic interactions with active site residues. Molecular dynamics simulations further confirmed the dynamic stability of the complexes.
