Pyrazolo[3,4-d]pyrimidines as the inhibitors of mycobacterial β-oxidation trifunctional enzyme

Tuberculosis, one of the oldest known human diseases, is still one of the major causes of mortality. Mycobacterium, a genus of Actinobacteria, is responsible for tuberculosis (Mycobacterium tuberculosis) and leprosy (Mycobacterium leprae). Because of producing high toxicity and resistance of existing drugs, the antitubercular drugs with less toxicity, potential activity and safer therapeutic profiles is an urgent need. Pyrazolo[3,4-d]pyrimidine compounds show various pharmacological activities including antitubercular. Molecular docking studies of eight pyrazolo[3,4-d]pyrimidine derivatives have been carried out with the mycobacterial beta-oxidation trifunctional enzyme (mtTFE) using Autodock and Glide docking protocols. The docking results demonstrate good binding capabilities of these molecules with mtTFE. Molecular dynamics simulations of the best docked complexes of the compounds demonstrating better binding affinities and satisfactory ADME properties have been carried out using DESMOND for 10.0 ns duration. The average RMSD variation and simulation interaction study indicate that the complexes remain stable during the course of dynamics. However, molecules 6 and 7 exhibit better stability than other molecules and are the suitable candidates to be carried forward as a potential lead in the discovery of drugs to contest tuberculosis.