Docking of phosphonate and trehalose analog inhibitors into M. tuberculosis mycolyltransferase Ag85C: Comparison of the two scoring fitness functions GoldScore and ChemScore, in the GOLD software

Abstract

The Ag85 family enzymes are responsible for the synthesis of cell wall components in mycobacterial species. Inhibitors to these enzymes are potential antimycobacterial agents. We have carried out the docking of phoshonate and trehalose analog inhibitors into the three dimensional structure of mycolyltransferase enzyme, Ag85C of M. tuberculosis using the GOLD software. The inhibitor binding positions and affinity were evaluated using both the scoring fitness functions- GoldScore and ChemScore. We observed that the inhibitor binding position identified using the GoldScore was marginally better than the ChemScore. A qualitative agreement between the reported experimental biological activities (IC50) and the GoldScore was observed. We identified that amino acid residues Arg541, Trp762 are important for inhibitor recognition via hydrogen bonding interactions. This information can be exploited to design Ag85C specific inhibitors.

Figure 1

(a) A list of 17 phosphonate inhibitors docked into the active site of mycolyltransferase, Ag85C. The reported Ic50 values of the corresponding molecules are also indicated. (b) A schematic representation of the phosphonate inhibitors with least Ic50 values

Figure 2

GoldScore based interactions of molecules (a) 3c (b) 4a (c) 5e and (d) 6b, docked into the active site of mycolyltransferase, Ag85C

Figure 3

ChemScore based interactions of molecules (a) 3c (b) 4a (c) 5e and (d) 6b, docked into the active site of mycolyltransferase, Ag85C

Figure 4

(a) GoldScore based docking of phosphonate inhibitors into the mycolyltransferase, Ag85C (b) ChemScore based docking of phosphonate inhibitors into the mycolyltransferase, Ag85C

Figure 5

(a) A list of 9 trehalose analog inhibitors docked into the active site of mycolyltransferase, Ag85C. The reported MIC values of the corresponding molecules are also indicated (b) A schematic representation of the trehalose analog inhibitors with least MIC values

Figure 6

GoldScore based interactions of molecules (a) 11b (b) 15a and (c) 18b docked into the active site of mycolyltransferase, Ag85C

Figure 7

ChemScore based interactions of molecules (a) 11b (b) 15a and (c) 18b docked into the active site of mycolyltransferase, Ag85C