Tuberculosis (TB) is a major cause of death worldwide and kills 1.5 million people per annum, thereby persisting as a challenge for the scientific community. Although the Directly Observed Treatment, Short Course chemotherapy (DOTS) is an internationally recommended approach for TB, the treatment regimen is long and arduous, making patient compliance difficult. This has led to growing cases of antibiotic confrontation, making a need for the identification of novel drug lead(s) against new targets identified in Mycobacterium tuberculosis (M.tb.). Current study was undertaken with this objective directed towards the identification of potential drug candidate(s) for TB therapy using an in silico approach against PKS18, a mycobacterial enzyme essential for its intracellular survival, pathogenicity and drug resistance. In the present study, 672 natural terpenoids from plants, algae, bacteria, fungi and marine sponges were compiled and put through in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis to explore their pharmacokinetic properties. Pharmacokinetic analyses revealed that 18 plants-derived and 1 marine sponge derived natural compounds satisfy all the ADMET descriptors as well as those of Lipinskis Rule of Five. These natural compounds docked successfully within the active site of type III polyketide synthase18 (PKS18) and exhibited low binding energy indicating high affinity. In addition, docking was also performed with commercially available first line TB drugs such as rifampicin, isoniazid, ethambutol and pyrazinamide to compare the binding efficacy with that of the selected natural compounds. Of the compounds tested, vulgarin showed the best docking profile, followed by alisiaquinone A, 12-Deoxyphorbol-13-angelate-20-acetate and cynaropicrin.
Key words: Tuberculosis, terpenoids, molecular docking, ADMET and type III polyketide synthase18.
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