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.
Highlights
Tuberculosis is an infection caused by the bacterium Mycobacterium tuberculosis
[4] Mycolic acid biosynthesis is known to be essential for mycobacterium growth, in particular trehalose mycolates aid in virulence of the organism and the structure of mycolates has been found to be important for initial replication and persistence in vivo
[5] A mutated M. tuberculosis strain lacking the functional Ag85C gene showed a 40% decrease in the amount of cell wall linked mycolic acids indicating its role in cell wall synthesis
Summary
It is a major disease infecting two billion people, or approximately one-third of the world’s population These numbers are rising in the developed countries due to the compromised immune systems, typically as a result of immunosuppressive drugs. In M. tuberculosis, a major secreted protein complex, antigen 85, constitutes three proteins antigen 85A, 85B and 85C [1] that are responsible for the synthesis of cell envelope These enzymes catalyze the transfer of mycolyl residue from one molecule of α, α’ trehalosemonomycolate (TMM) to another TMM leading to the formation of α, α’ trehalosedimycolate (TDM) [2] and are termed mycolyltransferases. A series of 6,6’-bis(sulfonamido), N,N’-dialkylamino and related derivatives of 6,6’-dideoxytrehalose were designed and synthesized to inhibit the Ag85 complex. [7]
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