Structure-based identification of natural compound inhibitor against M. tuberculosis thioredoxin reductase: insight from molecular docking and dynamics simulation.

Structure-based identification of natural compound inhibitor against M. tuberculosis thioredoxin reductase: insight from molecular docking and dynamics simulation.

Publication date: Jun 22, 2020

Antioxidant systems of M. tuberculosis (Mtb) play an important role in providing resistance in the hostile environment of mononuclear phagocytes. Thioredoxin system is a known antioxidant system that consists of three copies of thioredoxins (Trxs) and a single copy of thioredoxin reductase (TrxR). TrxR has been validated as an essential gene known to be involved in the reduction of peroxides, dinitrobenzenes and hydroperoxides, and is crucial in maintaining the survival of Mtb in macrophages. Recently, it has been demonstrated to be a druggable target. In this study, molecular docking was applied to screen more than 20,000 natural compounds from the Traditional Chinese Medicine database. Theoretical calculation of ?G by the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) methods indicated two top-hit compounds that bind with a high affinity to the allosteric site, consisting of a hinge region, of TrxR. Further, stability and binding analysis of both compounds were carried out with molecular dynamics simulation. An analysis of conformational variation by principal component analysis (PCA) and protein contact network (PCN) uncovered the conformational changes in the compound-bound forms of protein. The NADPH domain formed many new interactions with the FAD domain in the compound-bound form, signifying that the binding may render an effect on the protein structure and function. Our results suggest that these two compounds could potentially be used for structure-based lead inhibitors against TrxR. The inhibitor selected as lead compound will be used further as a scaffold to optimize as novel anti-tuberculosis therapeutic.Communicated by Ramaswamy H. Sarma.

Concepts Keywords
Affinity Affinity allosteric site
Allosteric Site Anti tuberculosis
Antioxidant Chemistry
Boltzmann Physical sciences
Dyn Branches of biology
FAD Drug discovery
Hinge Thioredoxin
Hydroperoxides Bioinformatics
Inhibitor Protein structure
Lead Compound Antioxidant
Macrophages Docking
Molecular Docking Allosteric regulation
Molecular Dynamics Selenium
NADPH Reductase
Peroxides Simulation
Phagocytes
Protein
Simulation
Thioredoxin
Thioredoxin Reductase
Traditional Chinese
Tuberculosis

Semantics

Type Source Name
drug DRUGBANK Thioredoxin
pathway KEGG Tuberculosis
disease MESH tuberculosis
drug DRUGBANK Pidolic Acid
drug DRUGBANK Flavin adenine dinucleotide

Original Article

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