Predictive Binding Affinity of Plant-Derived Natural Products Towards the Protein Kinase G Enzyme of Mycobacterium tuberculosis (MtPknG).

Qasaymeh Qasaymeh,Rotondo Rotondo,Oosthuizen Oosthuizen,Lall Lall,Seidel Seidel

doi:10.3390/plants8110477

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a growing public health concern worldwide, especially with the emerging challenge of drug resistance to the current drugs. Efforts to discover and develop novel, more effective, and safer anti-TB drugs are urgently needed. Products from natural sources, such as medicinal plants, have played an important role in traditional medicine and continue to provide some inspiring templates for the design of new drugs. Protein kinase G, produced by M. tuberculosis (MtPKnG), is a serine/threonine kinase, that has been reported to prevent phagosome-lysosome fusion and help prolong M. tuberculosis survival within the host’s macrophages. Here, we used an in silico, target-based approach (docking) to predict the interactions between MtPknG and 84 chemical constituents from two medicinal plants (Pelargonium reniforme and Pelargonium sidoides) that have a well-documented historical use as natural remedies for TB. Docking scores for ligands towards the target protein were calculated using AutoDock Vina as the predicted binding free energies. Ten flavonoids present in the aerial parts of P. reniforme and/or P. sidoides showed docking scores ranging from −11.1 to −13.2 kcal/mol. Upon calculation of all ligand efficiency indices, we observed that the (−ΔG/MW) ligand efficiency index for flavonoids (4), (5) and (7) was similar to the one obtained for the AX20017 control. When taking all compounds into account, we observed that the best (−ΔG/MW) efficiency index was obtained for coumaric acid, coumaraldehyde, p-hydroxyphenyl acetic acid and p-hydroxybenzyl alcohol. We found that methyl gallate and myricetin had ligand efficiency indices superior and equal to the AX20017 control efficiency, respectively. It remains to be seen if any of the compounds screened in this study exert an effect in M. tuberculosis-infected macrophages.

Highlights

Tuberculosis (TB), an infectious disease which mainly affects the lungs and is caused by the bacterium Mycobacterium tuberculosis, has plagued humans since antiquity [1]
Upon calculation of all ligand efficiency indices, we observed that the (−∆G/molecular weight (MW)) ligand efficiency index for flavonoids (4), (5) and (7) was similar to the one obtained for the AX20017 control
Knowing the nature of the key amino acid residues involved in the binding [43], we employed a rigid ligand docking approach to predict the affinity of each natural product from Pelargonium towards MtPknG

Summary

Introduction

Tuberculosis (TB), an infectious disease which mainly affects the lungs and is caused by the bacterium Mycobacterium tuberculosis, has plagued humans since antiquity [1]. Health Organisation estimated that there were 10 million TB cases worldwide, which resulted in a mortality rate of 1.6 million. The treatment of TB necessitates complex drug regimens, with adverse effects and interactions, and is associated with poor patient compliance. Patients with MDRor XDR-TB require a lengthy course of a combination of drugs that are more expensive, more toxic, and not always effective [2]. With the continuous increase in the number of drug-resistant TB cases, it is vital to identify drugs that could inhibit new druggable targets in M. tuberculosis [3,4,5,6,7,8]. Eleven different serine/threonine protein kinases have been reported in mycobacteria, including protein kinase

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