Identification of natural potent inhibitors against Mycobacterium tuberculosis isocitrate lyase: an in silico study.

Ali A Rabaan, Mohammed Garout, Mustafa A Najim, Mohammed Alissa, Muhammad A Halwani, Safaa A Turkistani, Roua A Alsubki, Abdulsalam Alawfi, Amer Alshengeti, Nawal A Al Kaabi, Thikrayat Q Alqazih, Ali A Aseeri, Afnan S Bahitham, Manal A Alsubaie, Mohammed Aljeldah

Journal: Molecular diversity 2024;28(5):2783-2799

PMID: 37578620

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Abstract

Tuberculosis (TB) is a global burden to humanity due to its adverse effects on health and society since time is not clearly defined. The existence of drug-resistant strains and the potential threat posed by latent tuberculosis act as strong impetuses for developing novel anti-tuberculosis drugs. In this study, various flavonoids were tested against the Mycobacterium tuberculosis (Mtb) Isocitrate Lyase (ICL), which has been identified as an authorised therapeutic target for treating Mtb infection. Using in silico drug discovery approach, a library of 241 flavonoid compounds was virtually screened against the binding pocket of the crystalline ligand, the VGX inhibitor, in the Mtb ICL protein. As a result, the top four flavonoids were selected based on binding score and were further considered for redocking and intermolecular contact profiling analysis. The global and local fluctuations in the protein and ligand structure were analysed using their root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values obtained from the GROMACS generated 100 ns molecular dynamics (MD) simulation trajectories. The end-state binding free energy was also calculated using the MMPBSA approach for all the respective docked complexes. All four selected compounds exhibited considerable stability and affinity compared to control ligands, i.e. VGX inhibitor; however, Vaccarin showed the highest stability and affinity against the Mtb ICL protein active site, followed by the Genistin, Glabridin, and Corylin. Therefore, this study recommends selected flavonoids for in vitro and in vivo experimental studies to check their potency and efficacy against Mtb.

Address: Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, 31311, Saudi Arabia. [email protected].; College of Medicine, Alfaisal University, Riyadh, 11533, Saudi Arabia. [email protected].; Department of Public Health and Nutrition, The University of Haripur, Haripur, 22610, Pakistan. [email protected].; Department of Medical Microbiology, Faculty of Medicine, Al Baha University, Al Baha, 4781, Saudi Arabia.; Department of Community Medicine and Health Care for Pilgrims, Faculty of Medicine, Umm Al-Qura University, Makkah, 21955, Saudi Arabia.; Fakeeh College for Medical Science, Jeddah, Saudi Arabia.; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11362, Saudi Arabia.; Department of Pediatrics, College of Medicine, Taibah University, Al-Madinah, 41491, Saudi Arabia.; Department of Infection Prevention and Control, Prince Mohammad Bin Abdulaziz Hospital, National Guard Health Affairs, Al-Madinah, 41491, Saudi Arabia.; Department of Medical Laboratories Technology, College of Applied Medical Sciences, Taibah University, Madinah, 41411, Saudi Arabia.; College of Medicine and Health Science, Khalifa University, Abu Dhabi, 127788, United Arab Emirates.; Sheikh Khalifa Medical City, Abu Dhabi Health Services Company (SEHA), Abu Dhabi, 51900, United Arab Emirates.; Microbiology Laboratory Department, King Fahad Specialist Hospital, Dammam, 32253, Saudi Arabia.; Biochemistry Laboratory Department, King Fahad Specialist Hospital, Dammam, 32253, Saudi Arabia.; Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia.; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hafr Al Batin, Hafr Al Batin, 39831, Saudi Arabia. [email protected].

DOI: 10.1007/s11030-023-10711-w

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https://doi.org/10.1007/s11030-023-10711-w

MeSH Terms: Isocitrate Lyase, Mycobacterium tuberculosis, Flavonoids, Molecular Docking Simulation, Molecular Dynamics Simulation, Enzyme Inhibitors, Antitubercular Agents, Computer Simulation, Ligands, Protein Binding