Docking Analysis of Potent Inhibitors of β-ketoacyl-acyl Carrier Protein Synthase III as Potential Antimicrobial Agents

According to data of the World Health Organization, Tuberculosis (TB) caused by Mycobacterium tuberculosis, is considered to be the most chronic communicable disease in the World especially in Asia and Africa. This situation was made worse by the emergence of multi drug resistant TB (MDR-TB) and the increasing number of HIV-positive TB cases. Worldwide, TB accounts for approximately one-fourth of HIV-related deaths and is the leading cause of death in HIV-infected adults in developing countries, thus an urgent need exists for the development of new antimycobacterial agents with a unique mechanism of action. Mycobacterium tuberculosis FabH, an essential enzyme in the mycolic acid biosynthetic pathway, is an attractive target for novel anti-tubercolosis agents. A series of pyrazolone linked with isonicotinic acid hydrazide were computationally designed and energy minimized. The molecular properties were calculated from suitable computational tools. These ligands were investigated for drug like properties by calculating Lipinski's rule of five using molinspiration. All of the derivatives showed a zero violations of the rule of 5 which indicates good bioavailability. The positive bioactivity score of the derivative were also in agreement with their probability of drug likeness. These compounds were docked into the active site of FabH, (PDB code-1HZP) using Argus lab docking software which showed good binding energy for the enzyme, when compared with the binding energies of standard drug isoniazid -6.17kcal/mol.) Among all the designed ligands, the ligand II and V showed more binding energy values (-8.68 and -8.86Kcal/mol) . In future we planned to synthesise these ligand and to screen for their anti TB activity.