High throughput screening against pantothenate synthetase identifies amide inhibitors against Mycobacterium tuberculosis and Staphylococcus aureus .

Abstract: Pantothenate is a crucial enzyme for the synthesis of coenzyme A and acyl carrier protein in Mycobacterium tuberculosis and Staphylococcus aureus . It is indispensable for the growth and survival of these bacteria. Amides analogs are designed and have been used as inhibitors of pantothenate synthetase. Molecular docking approach has been used to design and predict the drug activity of molecule to the specific disease. In this work, more than hundred amides have been screened by Discovery Studio molecular docking programme to search best suitable molecule for the treatment of Mycobacterium tuberculosis . Pharmacophore generation has been done to recognize the binding modes of inhibitors in the receptor active site. To observe the stability and flexibility of inhibitors molecular dynamics (MD) simulation has been done; Lipinski's rule of five protocols is followed to screen drug likeness and ADMET (absorption, distribution, metabolism, excretion and toxicity) filtration is also used to value toxicity. DFT computation of optimized geometry and derivation of MOs has been used to correlate the drug likeness. The small difference in energy between HOMO and LUMO may help to activate the drug in the protein environment quickly. 2-Hydroxy-5-[(E)-2-{4-[(prop-2-enamido)sulfonyl]phenyl}diazen-1-yl]benzoic acid (M1) shows best theoretical efficiency against Mycobacterium tuberculosis (MTB) pantothenate synthetase and so does 2-hydroxy-5-[(E)-2-{4-[(2-phenylacetamido)sulfonyl]phenyl}diazen-1-yl]benzoic acid (M2) against Staphylococcus aureus pantothenate synthetase. These compounds also bind to Adenine-Thymine region of tuberculosis DNA.