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

Abstract

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.

Keywords: ADMET; Heterocyclic amide compounds; MD simulation; Molecular docking; Pantothenate synthetase inhibitors; Structure based drug design.

Fig. 1

Activity of pantothenate synthetase

Fig. 2

Docked comprehensive perception of MTB pantothenate synthetase and M1 after docking. a p.s is represented by ribbon and M1 is represented by stick and coloured according to elements. b secondary structure of p.s represented by hydrophobic surface and M1 represented is by stick model, c interactions of M1 with p.s amino acids. Bonds are in dots. M1 surrounding amino acids are in three letters code, represented in blue

Fig. 3

Docked comprehensive perception of pantothenate synthetase and C1 interaction after docking. Picture legends representation are same as Fig. 1

Fig. 4

Docked comprehensive perception M2 and Staphylococcus aureus pantothenate synthetase after docking. Picture legends representation is same as Fig. 2

Fig. 5

Comprehensive perception of C2 and Staphylococcus aureus pantothenate synthetase interaction after docking. Picture legends representation are same as Fig. 2

Fig. 6

a, b HOMO and LUMO plots of M1. The positive electron density has been shown in green color while negative in violet. c, d HOMO and LUMO plots of C1. The positive electron density has been shown in red color while negative in blue

Fig. 7

The result of pharmacophore features of M1 based on receptor-ligand pharmacophore generation. The hydrogen bond acceptor, hydrogen bond donor, positive ionizablefeature, aromatic ring and negative ionizable features are shown as green, orange and blue respectively

Fig. 8

The result of pharmacophore features of M2 based on receptor-ligand pharmacophore generation. The hydrogen bond acceptor, hydrogen bond donor, positive ionizablefeature, aromatic ring and negative ionizable features are shown as green, orange, and blue respectively

Fig. 9

M1 interaction with Tuberculosis’s DNA in minor groove. a Drug is represented by stick and double helical DNA structure is represented by ladder and rings, b double helical structure of DNA represented by M1 represented by stick model and are coloured according to elements, c interactions of ligand with DNA base pairs (A, T, G, C); the interaction types. Hydrogen bonds are in green. Ligand surrounding base pairs are in three letters code represented in black

Fig. 10

Shows bond energy graph of M1, other four molecules of Table 3 and C1 with pantothenate synthetase of Mycobacterium tuberculosis. Bond energy and number of trajectory frames are plotted along X- and Y-axis respectively. Best docked molecule is in blue and C1 is in pink. (Series numbers are maintained as in Table 3)

Fig. 11

Shows bond energy graph of M2 with pantothenate synthetase of S. aurues. X axis and Y-axis represent the bond energy and number of trajectory frames respectively. Best docked molecule is in pink and C2 is in blue. (Series numbers are maintained as in Table 4)

Fig. 12

Shows bond energy graph of 2-hydroxy-5-[(E)-2-{4-[(prop-2-enamido) sulfonyl] phenyl} diazen-1-yl] benzoic acid and C1 with DNA of Mycobacterium tuberculosis. X-axis and Y-axis represent bond energy and number of trajectory frames respectively. Best docked molecule is in green and C1 is in violet

Fig. 13

Shows results of molecular dynamics, last conformation (structure) superimposed (red) with first conformation (blue) of pantothenate synthetase of Mycobacterium tuberculosis