Molecular Docking, Free Energy Calculations, ADMETox Studies, DFT Analysis, and Dynamic Simulations Highlighting a Chromene Glycoside as a Potential Inhibitor of PknG in Mycobacterium tuberculosis

Muharib Alruwaili ^1* Tilal Elsaman ^2* Magdi Awadalla Mohamed ² Abozer Y. Elderdery ¹ Jeremy Mills ³ Yasir Alruwaili ¹ Siddiqa M A Hamza ⁴ Salma Elhadi Ibrahim Mekki ⁵ Hazim Abdullah Alotaibi ⁶ Maily J Alrowily ⁷ Maryam Musleh Althobiti ⁸

• ¹ Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia
• ² Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
• ³ School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom
• ⁴ Department of Pathology, Umm Alqura University, Algunfuda, Saudi Arabia
• ⁵ Department of Physiology, College of Medicine in alqunfudah, Umm alqura Universit, alqunfudah, Saudi Arabia
• ⁶ Department of Internal Medicine and Oncology, Prince Mohammed Medical City, Hail, Saudi Arabia
• ⁷ Consultant -Research Center, Aljouf Health Cluster,, Aljouf, Saudi Arabia
• ⁸ Department of Clinical Laboratory Science, College of Applied Medical Science, Shaqra University,, Shaqra 11961, Saudi Arabia

Introduction: Tuberculosis (TB), caused by the Mycobacterium tuberculosis (M.tb), remains a serious medical concern globally. Resistant M.tb strains are emerging, partly because M.tb can survive within alveolar macrophages, resulting in persistent infection. Protein kinase G (PknG) is a mycobacterial virulence factor that promotes the survival of M.tb in macrophages. Targeting PknG could offer an opportunity to suppress the resistant M.tb strains. Methods: In the present study, multiple computational tools were adopted to screen a library of 460,000 molecules for potential inhibitors of PknG of M.tb. Results and Discussions: Seven Hits (1‒7) were identified with binding affinities exceeding that of the reference compound (AX20017) towards the PknG catalytic domain. Next, the ADMETox studies were performed to identify the best hit with appropriate drug-like properties. The chromene glycoside (Hit 1) was identified as a potential PknG inhibitor with better pharmacokinetic and toxicity profiles rendering it a potential drug candidate. Furthermore, quantum computational analysis was conducted to assess the mechanical and electronic properties of Hit 1, providing guidance for further studies. Molecular dynamics simulations were also performed for Hit 1 against PknG, confirming the stability of its complex. In sum, the findings in the current study highlight Hit 1 as a lead with potential for development of drugs capable of treating resistant TB.