title: Computational Elucidation of Structural Basis for Ligand Binding with Mycobacterium tuberculosis Glucose-1-Phosphate Thymidylyltransferase (RmlA).
abstract: Glucose-1-Phosphate Thymidylyltransferase (RmlA) is one of the enzymes in rhamnose biosynthesis pathway, where rhamnose acts as linker of peptidoglycan and arabinogalacton in the cell wall, therefore RmlA is a potential enzyme for the survival of Mycobacterium tuberculosis (Mtb). To go into the depth of the structure for exploring binding regions, homology model of RmlA was built in Prime, Schrodinger v9.2. The model with lowest Discrete Optimized Potential Energy (DOPE) score of -35524.17 kcal/mol and RMSD of 0.1 Å with the template (1H5R_B) was subjected to Molecular Dynamics Simulation (MDS) for 5 ns to achieve its stable folding state. The tertiary structure of the proposed model is composed of α/β/α sandwich type protein with quasi-Rossmann type folding pattern. The substrate, deoxy Thymidine tri phosphate (dTTP) comprises of triphosphate (R1) and methyl (R2) side chains where, R1 is highly essential for the survival of Mtb. Therefore, nineteen side chain analogues of dTTP were designed by substituting R1 and R2 chain of dTTP using Combi Glide, Schrodinger v9.2 and docked with the target RmlA protein. Out of which two analogues such as, 6-[(2R,3S,5R)-5-[5-(2- aminoethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl]-3-hydroxyoxolan-2 yl] hexanoic acid (COMP- 11) and 4-(2-{1-[(1S,3S,4S)-3-(5-carboxypentyl)-4-hydroxy-2-methylidenecyclopentyl]-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-5-yl}ethyl)morpholin-4-ium (COMP-12) showed the highest GLIDE score (-12.55 Kcal/mol and -11.58 Kcal/mol respectively) than that of substrate (-9.725 Kcal/mol). During simulations, hydrogen bonding profile between the two top hits and protein ranges up to 5 strong polar contacts which were much stronger than that of substrate. Similarly, the computational binding free energy of both the analogues was found to be less than -70 Kcal/mol which is much lower than that of substrate (-52.84 Kcal/mol). All these results suggest that these two compounds have more stable interaction than that of substrate inside the solvent condition and can be used as competitive inhibitors.
authors.forename: Rani
authors.initials: R
authors.lastname: Mansuri
authors.forename: Md Yousuf
authors.initials: MY
authors.lastname: Ansari
authors.forename: Jagbir
authors.initials: J
authors.lastname: Singh
authors.forename: Sindhuprava
authors.initials: S
authors.lastname: Rana
authors.forename: Sahil
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Bio Medical Informatics Division, Rajendra Memorial Research Institute of Medical Sciences, Agam kuan, Patna-800007, India.
authors.forename: Ganesh C
authors.initials: GC
authors.lastname: Sahoo
authors.forename: Manas R
authors.initials: MR
authors.lastname: Dikhit
authors.forename: Pradeep
authors.initials: P
authors.lastname: Das
mesh_terms: D008024:Ligands; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000737:chemistry*; D013942:Thymine Nucleotides / Q000737:chemistry
chemical_list: D008024:Ligands; D013942:Thymine Nucleotides; D009713:Nucleotidyltransferases; C020587:glucose-1-phosphate thymidylyltransferase; C024157:thymidine 5'-triphosphate