Identification of novel leads applying in silico studies for Mycobacterium multidrug resistant (MMR) protein

• Published in: Journal of biomolecular structure & dynamics Vol. 32; no. 12; pp. 1889 - 1906
• Main Authors: Malkhed, Vasavi, Mustyala, Kiran Kumar, Potlapally, Sarita Rajender, Vuruputuri, Uma
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.12.2014
• Subjects: Amino Acid Sequence; Antibiotics, Antitubercular - chemistry; Bacterial Proteins - chemistry; Catalytic Domain; Computer Simulation; Databases, Chemical; docking studies; Drug Resistance, Multiple, Bacterial; homology modeling; Humans; Ligands; Molecular Docking Simulation; Molecular Sequence Data; multidrug efflux; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - chemistry; Mycobacterium tuberculosis; Mycobacterium tuberculosis - metabolism; Protein Conformation; Small Molecule Libraries - chemistry; small multidrug resistant protein family; small multidrug resistant protein family; multidrug efflux; docking studies; homology modeling; Mycobacterium tuberculosis
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2013.842185

Multidrug efflux mechanism is the main cause of intrinsic drug resistance in bacteria. Mycobacterium multidrug resistant (MMR) protein belongs to small multidrug resistant family proteins (SMR), causing multidrug resistance to proton (H + )-linked lipophilic cationic drug efflux across the cell membrane. In the present work, MMR is treated as a novel target to identify new molecular entities as inhibitors for drug resistance in Mycobacterium tuberculosis. In silico techniques are applied to evaluate the 3D structure of MMR protein. The putative amino acid residues present in the active site of MMR protein are predicted. Protein-ligand interactions are studied by docking cationic ligands transported by MMR protein. Virtual screening is carried out with an in-house library of small molecules against the grid created at the predicted active site residues in the MMR protein. Absorption distribution metabolism and elimination (ADME) properties of the molecules with best docking scores are predicted. The studies with cationic ligands and those of virtual screening are analysed for identification of new lead molecules as inhibitors for drug resistance caused by the MMR protein.