Molecular docking, molecular dynamics and MM/PBSA studies of FDA approved drugs for protein kinase a of Mycobacterium tuberculosis; application insights of drug repurposing

Tuberculosis (TB) is a deadly disease, and novel treatment strategies are required to combat it. Repurposing of existing Food and Drug Administration (FDA) approved drugs against Mycobacterium tuberculosis (Mtb) proteins could be beneficial for TB treatment. Protein kinase A (PknA) is one of the Serine/Threonine protein kinases (STPKs) of Mtb, and is an essential drug target, as it phosphorylates a number of proteins important for mycobacterial survival. In this study, through a molecular docking approach, we have screened 3176 FDA approved drugs against PknA and determined binding efficacy. Interestingly, the topmost compounds which have an improved docking score were found to be Vitamin B2 based compounds (ZINC3831425 and ZINC1769096) which can potentially bind and inhibit PknA. Molecular dynamics (MD) studies were performed to evaluate the stability of the docked complexes. Free energy of binding for the compounds docked with PknA was assessed by using the MM/PBSA method. Nutritional supplements have proven to be beneficial in treating TB. Thus, we hypothesize that Riboflavin or Vitamin B2 based compounds may inhibit PknA of Mtb, and could be used as an adjunct for the treatment of TB. Keywords: Mycobacterium tuberculosis, PknA, Molecular docking and dynamics, Riboflavin, Repurposing of drugs, Free energy calculation