Identification of new potential Mycobacterium tuberculosis shikimate kinase inhibitors through molecular docking simulations

• Published in: Journal of molecular modeling Vol. 18; no. 2; pp. 755 - 764
• Main Authors: Vianna, Carolina Pasa, de Azevedo, Walter F.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.02.2012
• Subjects: Algorithms; Antitubercular Agents - chemistry; Binding Sites; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Computer Simulation; Humans; Ligands; Models, Molecular; Molecular Medicine; Mycobacterium tuberculosis - enzymology; Original Paper; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Structure, Secondary; Theoretical and Computational Chemistry; Shikimate kinase; Virtual screening; Shikimate pathway; Tuberculosis; Molecular docking
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-011-1113-5

Tuberculosis (TB) is the major cause of human mortality from a curable infectious disease, attacking mainly in developing countries. Among targets identified in Mycobacterium tuberculosis genome, enzymes of the shikimate pathway deserve special attention, since they are essential to the survival of the microorganism and absent in mammals. The object of our study is shikimate kinase (SK), the fifth enzyme of this pathway. We applied virtual screening methods in order to identify new potential inhibitors for this enzyme. In this work we employed MOLDOCK program in all molecular docking simulations. Accuracy of enzyme-ligand docking was validated on a set of 12 SK-ligand complexes for which crystallographic structures were available, generating root-mean square deviations below 2.0 Å. Application of this protocol against a commercially available database allowed identification of new molecules with potential to become drugs against TB. Besides, we have identified the binding cavity residues that are essential to intermolecular interactions of this enzyme.