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

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