Identification of Small Molecular Inhibitors for Efflux Protein: DrrA of Mycobacterium tuberculosis

• Published in: Cellular and molecular bioengineering Vol. 9; no. 1; pp. 190 - 202
• Main Authors: Mustyala, Kiran Kumar, Malkhed, Vasavi, Chittireddy, Venkata Ramana Reddy, Vuruputuri, Uma
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.03.2016; Springer Nature B.V
• Subjects: ABC transporters; Adenosine triphosphatase; Amino acids; Bacteria; Binding; Biological and Medical Physics; Biomaterials; Biomedical Engineering and Bioengineering; Biomedical Engineering/Biotechnology; Biophysics; Cell Biology; Drugs; Efflux; Engineering; Inhibitors; Ligands; Mycobacterium tuberculosis; Proteins; Tuberculosis; Virtual screening; Doxorubicin resistance ATP-binding protein (DrrA); ABC transporters (ATP binding cassette); Comparative modelling
• ISSN: 1865-5025; 1865-5033
• DOI: 10.1007/s12195-015-0427-2

Tuberculosis (TB) is caused by intracellular bacterial pathogen Mycobacterium tuberculosis . Development of multidrug resistant strains is one of the major challenges for current TB therapy. The Doxorubicin resistance ATP-binding protein DrrA (DrrA) is an efflux protein. DrrA extrudes the drug molecules from the cytoplasm, which reduces the drug concentration inside the cell and develops resistance to the drugs. The efflux mechanism is initiated by a complex formation between DrrA and DrrB proteins. In the present work inhibitors are identified to inhibit the binding of DrrA with DrrB protein. The structure of DrrA protein is generated, validated and active site studies are taken up using standard in silico protocols. The Virtual screening studies are performed and ADME properties are predicted to identify competitive inhibitors for DrrA protein at DrrB binding site. The study discloses amino acid residues Gln198, Leu200, Glu201, Asp 214, Glu237 and Ile238 are important for binding in the DrrA protein with ligand molecules. These ligand molecules can be treated as potent inhibitors for DrrA protein.