In-silico identification of phytocompounds as inhibitors of key enzymes in Shikimate pathway of Mycobacterium tuberculosis for discovery of new lead molecules

Abstract

Tuberculosis is one of the most lethal respiratory infections caused by the microorganism Mycobacterium tuberculosis. Despite the availability of several drugs to treat TB, numerous reports have demonstrated the cause and emergence of multidrug resistance of M. tuberculosis. Hence, the need of developing effective anti-TB therapeutics against multidrug-resistant strains has always been cardinal attention for the past two decades. In this study, to identify potent anti-tuberculosis drugs, two enzymes namely, 3-dehydroquinate synthase and 3-dehydroquinate dehydratase of mycobacterial Shikimate pathway were selected as drug targets for inhibiting their regulatory mechanisms. The medicinal plant Achyranthes aspera has been traditionally used in pulmonary infection. Therefore, the phytocompounds from this plant were selected for carrying out the computational evaluation of their binding affinities and drug-like properties against the selected enzymes. Molecular docking was done for 11 phytocompounds against these two enzymes (receptors) using AutoDock Vina software. The compounds which exhibited the highest binding affinities with targets were selected for pharmacokinetic analysis, bioactivity prediction and toxicity calculation. From the docking study, it was concluded that the compound-9 (ecdysterone 2,3-acetonide 22-O-benzoate) and compound-2 (2,3,14,20,25-pentahydroxy-6-oxocholest-7-en-22-yl benzoate) showed the highest binding affinities with the enzymes3-dehydroquinate synthase and 3-dehydroquinate dehydratase, respectively. Eventually, both the compound exhibited similar druglikeness by obeying Lipinski’s rule of 5.
Keywords: Achyranthes aspera,Molecular docking, Shikimate pathway, Pharmacokinetics.