Computational exploration and anti-mycobacterial activity of potential inhibitors of Mycobacterium tuberculosis acetyl coenzyme A carboxylase as anti-tubercular agents

Acetyl Coenzyme A Carboxylase (AccD6) is a homodimeric protein which is involved in the carboxylation of acetyl coenzyme A to produce malonyl coenzyme A, which plays an important role in the biosynthesis of fatty acid chain. However, studies suggest that AccD6 in combination with AccA3 produces malonyl co-A. Certain herbicides are known to inhibit plant ACC. Among these herbicides, haloxyfop was found to inhibit AccD6 at IC50 of 21.1 +/- 1 mu M. In this study, we have performed molecular docking of the Maybridge database consisting of similar to 55,000 compounds in the active site of the protein with haloxyfop as a reference molecule, followed by molecular dynamics study and biological activity determination of prioritized compounds. Out of the nine compounds selected for biological evaluation, three compounds - CD07230, HTS08529 and KM08871 - were found to exhibit anti-mycobacterial activity.