A Virtual Screening Approach for Thymidine Monophosphate Kinase Inhibitors as Antitubercular Agents Based on Docking and Pharmacophore Models

Abstract

Docking and pharmacophore screening tools were used to examine the binding of ligands in the active site of thymidine monophosphate kinase of Mycobacterium tuberculosis. Docking analysis of deoxythymidine monophosphate (dTMP) analogues suggests the role of hydrogen bonding and other weak interactions in enzyme selectivity. Water-mediated hydrogen-bond networks and a halogen-bond interaction seem to stabilize the molecular recognition. A pharmacophore model was developed using 20 dTMP analogues. The pharmacophoric features were complementary to the active site residues involved in the ligand recognition. On the basis of these studies, a composite screening model that combines the features from both the docking analysis and the pharmacophore model was developed. The composite model was validated by screening a database spiked with 47 known inhibitors. The model picked up 42 of these, giving an enrichment factor of 17. The validated model was used to successfully screen an in-house database of about 500,000 compounds. Subsequent screening with other filters gave 186 hit molecules.

Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

“…Based on a restricted set of 47 inhibitors of TMPKmt modified on the 5-, 2'-, 3'-and 5'-positions of dTMP (described above), the groups of Gopalakrishnan and Desijaru have developed models either to perform virtual screening [39] or 3D-QSAR analysis [40]. Both approaches take advantage of the solved 3D-structure of TMPKmt with dTMP [11].…”

“…After its validation by screening a database of 2,000 molecules containing the training set of 47 molecules, the model was used for the virtual screening of 500,000 compounds. 186 molecules were further selected that could be categorized into five clusters [39].…”

The structure, properties, and nature of unconventional π halogen bond in the complexes of Al 4 2- and halohydrocarbons

“…Metrangolo et al presented a review on the great potential of halogen bonds in the design of new and high-value functional materials [14]. Nowadays it has come to light that this specific interaction has utilization in the context of drug design [12][13][14][15][16][17][18]. Auffinger and co-workers screened and assembled a data set of protein and nucleic acid structures to characterize the prevalence and geometry of halogen bonds in biological systems [12].…”

Optimization of Structure Based Virtual Screening Protocols Against Thymidine Monophosphate Kinase Inhibitors as Antitubercular Agents

“…Also, these molecules can be promising leads to treat tuberculosis by inhibiting DNA synthesis in M. tuberculosis. [4,[9][10][11][12][13][14][15] Several studies were reported for finding the relationship between TMPK Mtub and their inhibitors (usually dTMP) using crystallographic techniques. [4,7,8,16] Considering all available information about TMPK Mtub and its inhibitors, we devised our work in the paradigm of computational chemistry methods.…”